Cyclic monomer and dimer peptides having integrin antagonist activity

Abstract

The invention relates to C to N cyclized (C-N cyclic) monomer and dimer peptide molecules, as well as peptide dimers which are connected by linker moieties at the N terminus and the C terminus of each peptide subunit, which inhibit binding of 47 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, and show high selectivity against 41 binding.

Claims

1. A cyclic dimer compound comprising two peptide monomer subunits of Formula (VII):
Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.11-Xaa.sup.12-Xaa.sup.13-Xaa.sup.14 (Formula (VII)) or a pharmaceutically acceptable salt thereof, wherein one or both subunits comprises a disulfide bond, a lactam bond, an olefin bond, a triazole bond, a selenoether bond, a thioether bond, an amide bond, or a diselenide bond between Xaa.sup.4 and Xaa.sup.10, wherein: Xaa.sup.1 is absent, Ac, or any amino acid; Xaa.sup.2 is absent, Ac, or any amino acid; Xaa.sup.3 is absent, Ac, or any amino acid; Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10; Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidinoguanidino), Phe(4-carbamoyl), Cit, Phe(4-NH.sub.2), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His; Xaa.sup.6 is Ser, Ile, Gly, Thr or Ile; Xaa.sup.7 is Asp, D-Asp, Asp(OMe) or N-Me-Asp; Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr; Xaa.sup.9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pentyl Ala, N-hexyl Ala, cyclobutyl-Ala, cyclopentyl-Ala, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu; Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4; Xaa.sup.11 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, and Tic; Xaa.sup.12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, homoPhe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres; Xaa.sup.13 is absent or Pro or any amino acid; and Xaa.sup.14 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp, wherein the cyclic dimer compound comprises two linker moieties linking the two peptide monomer subunits via their C-termini and N-termini.

2. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, D-Orn, Cys, homocys, Pen, D-homoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and homoSer.

3. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein any one of Xaa, Xaa.sup.2 or Xaa.sup.3 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

4. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein the N-terminal amino acid and/or the C-terminal amino acid is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

5. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein the two linker moieties are selected from the group consisting of: DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da, and bifunctional linkers selected from the group consisting of di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, and bis-maleimides.

6. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein the C terminus of the first monomer subunit is joined to the C-terminus of the second monomer subunit via a first linker moiety, and the N-terminus of the first monomer subunit is joined to the N-terminus of the second monomer subunit via the second linker moiety to provide a cyclic formation.

7. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, comprising a disulfide bond between Xaa.sup.4 and Xaa.sup.10.

8. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, comprising a thioether bond between Xaa.sup.4 and Xaa.sup.10.

9. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, comprising N(alpha)methylation at one or more positions selected from the group consisting of Xaa.sup.3, Xaa.sup.5, Xaa.sup.7-Xaa.sup.9, and Xaa.sup.11-Xaa.sup.13.

10. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, further comprising acylation at one or more position selected from the group consisting of Xaa.sup.1-Xaa.sup.3 and Xaa.sup.11-Xaa.sup.14.

11. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1.

12. A method for treating a subject afflicted with a condition that is associated with a biological function of 47, wherein the method comprises administering to the subject the compound or pharmaceutically acceptable salt thereof of claim 1 or the composition of claim 11.

13. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein Xaa.sup.5 is N-Me-Arg, Xaa.sup.6 is Ser, Xaa.sup.7 is Asp, Xaa.sup.8 is Thr, and Xaa.sup.9 is Leu.

14. The cyclic dimer compound or pharmaceutically acceptable salt thereof of claim 1, wherein each of the monomer subunits comprises one of the following sequences: Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(-homo-Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-(-homo-Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-(-homo-Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); or Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu; wherein there is a disulfide bond between the two Pen residues of each subunit.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In order that the manner in which the above-recited and other features and advantages of the invention are obtained will be readily understood, a more particular description of the invention briefly described above will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered to be limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

(2) FIG. 1 is a schematic showing a cylic dimer peptide in accordance with a representative embodiment of the present invention.

(3) FIG. 2 is a diagram of an illustrative linker system that may be used to dimerize monomer subunits of peptides of the present invention. FIG. 2 shows a pair of integrin antagonist monomer subunits wherein the subunits are aligned and linked at their respective C-termini by a linker that connects two sulfur-containing amino-acids to form a peptide dimer linking sulfhydryl-to-sulfhydryl crosslinking of the present invention. In particular embodiments, the linker can comprise homobifunctional maleimide crosslinkers, di-halide, 1,2-Bis(bromomomethyl)benzene, 1,2-Bis(chloromomethyl)benzene, 1,3-Bis(bromomomethyl)benzene, 1,3-Bis(chloromomethyl)benzene, 1,4-Bis(bromomomethyl)benzene, 1,4-Bis(chloromomethyl)benzen 3,3-Bis-bromomethyl-biphenyl, or 2,2-Bis-bromomethyl-biphenyl. Certain haloacetyl crosslinkers contain an iodoacetyl or a bromoacetyl groups. These homo bifunctional linkers may contain spacers comprising PEG or an aliphatic chain.

(4) FIG. 3 is a chart demonstrating potency data for illustrative cyclic dimers, in accordance with various representative embodiment of the present invention. **<100 nM; ***=100-1000 nM; >1000 indicates greater than 1000 nM but less than or equal to 10,000 nM; >10,000 indicates greater than 10,000 nM but less than or equal to 100,000 nM. <180 indicates less than 180 min and >180 indicates greater than 180 min.

(5) FIG. 4 is a schematic showing a C-N cyclic monomer peptide molecule formed by C to N cyclization in accordance with a representative embodiment of the present invention.

(6) FIG. 5 is a schematic showing a C-N cyclic monomer peptide molecule of the invention further comprising an intramolecular bond. The C-N cyclic monomer shown in FIG. 5 is illustrative. Embodiments of the present invention include C-N cyclic monomers that an lack intramolecular bond between Xaa.sup.4 and Xaa.sup.10, or between corresponding amino acids.

SEQUENCE LISTING

(7) The amino acid sequences listed in the accompanying sequence listing are shown using three letter code for amino acids, as defined in 37 C.F.R. 1.822. Only the monomer subunit sequences are shown, however it is understood that the monomer subunits may be dimerized to form cyclic dimer peptide molecules, in accordance with the present teaching and as shown generally in FIG. 1. The monomer subunits are dimerized by a suitable linker moieties, as defined herein. The monomer subunits are shown having C- and N-termini that comprising free amine. Thus, dimerization occurs at both the C- and N-terminals via the respective free amines. Further, in some instances a terminal end of one or more monomer subunits is acylated with an acylating organic compound selected from the group consisting of 2-Methyl-4,4,4,-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyl, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid.

(8) In the accompanying sequence listing:

(9) SEQ ID NO: 1 shows a sequence of a C-N cyclic monomer peptide, a C-N cyclic monomer subunit of a C-N cyclic dimer, or a monomer subunit of a cyclic dimer compound.

(10) SEQ ID NO: 2 shows a sequence of a C-N cyclic monomer peptide, a C-N cyclic monomer subunit of a C-N cyclic dimer, or a monomer subunit of a cyclic dimer compound.

(11) SEQ ID NOs: 1-38, 46-52, 54-135, and 137-146 show amino acid sequences of C-N cyclic monomer peptides, or C-N cyclic monomer subunits or cyclic monomer subunits that are dimerized to form various C-N cyclic or cyclic dimer compounds in accordance with the present invention, wherein these sequences have been substituted with an N(alpha)methylated arginine.

(12) SEQ ID NO: 136 shows an amino acid sequence of a C-N cyclic monomer peptide, a C-N cyclic monomer subunit, or a cyclic monomer subunit that is dimerized to form a C-N cyclic dimer or cyclic dimer compound in accordance with the present invention, wherein this sequence has been substituted with an N(alpha)methylated lysine.

(13) SEQ ID NOs: 1-38 are general sequences that may be dimerized at their C- and N-terminuses to form various cyclic dimer compounds in accordance with the present invention, or may be linked at their C-termini and N-termini to form C-N cyclic monomer peptides or C-N cyclic dimer peptide subunits.

(14) SEQ ID NOs: 39-146 show amino acid sequences of monomer subunits that may be linked at their C- and N-terminuses with various linkers to form various cyclic dimer compounds in accordance with the present invention, or may be linked at their C-termini and N-termini to form C-N cyclic monomer peptides or C-N cyclic dimer peptide subunits.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(15) As used herein, the singular forms a, and and the include plural references unless the context clearly dictates otherwise.

(16) As used in the present specification the following terms have the meanings indicated:

(17) The term peptide refers broadly to a sequence of two or more amino acids joined together by peptide bonds. It should be understood that this term does not connote a specific length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring.

(18) The term DRP, as used herein, refers to disulfide rich peptides.

(19) The term dimer, as used herein, refers broadly to a peptide comprising two or more subunits, as described herein. Dimers of the present invention may include homodimers and heterodimers and function as integrin antagonists.

(20) The term cyclic dimer, or cyclic dimer peptide or cyclic peptide dimer or cyclic dimer compound as used herein, refers broadly to a peptide comprising two or more subunits, wherein the subunits are linked at their C- and N-terminuses using two linker moieties. Cyclic dimers of the present invention may include homodimers and heterodimers and function as integrin antagonists. Cyclic dimers of the present invention may also include symmetrical or asymmetrical linker moieties. In a cyclic dimer, linkers may link the N-termini of each subunit to each other, and the C-termini of each subunit to each other, or linkers may connect the N-terminal of one subunit to the C-terminal of the other subunit and vice versa.

(21) The term cyclized, as used herein, refers to a reaction in which one part of a polypeptide molecule becomes linked to another part of the polypeptide molecule to form a closed ring, such as by forming a disulfide bridge or other similar bond.

(22) The terms C-N cyclic peptide, C-N cyclic compound, or C-N cyclic monomer, as used herein, refer to a peptide molecule that is cyclized by a linkage from the C-terminus to the N-terminus.

(23) The term C-N cyclic dimer refers to a dimer of two C-N cyclized monomer peptides.

(24) The term L-amino acid, as used herein, refers to the L isomeric form of a peptide, and conversely the term D-amino acid refers to the D isomeric form of a peptide. The amino acid residues described herein are preferred to be in the L isomeric form, however, residues in the D isomeric form can be substituted for any L-amino acid residue, as long as the desired functional is retained by the peptide.

(25) The term NH.sub.2, as used herein, refers to the free amino group present at the amino terminus of a polypeptide. The term OH, as used herein, refers to the free carboxy group present at the carboxy terminus of a peptide. Further, the term Ac, as used herein, refers to Acetyl protection through acylation of the C- or N-terminus of a polypeptide. The term NH.sub.2 may also be used herein to refer to a C-terminal amide group.

(26) The term carboxy, as used herein, refers to CO.sub.2H.

(27) The term isotere or isostere replacement, as used herein, refers to any amino acid or other analog moiety having chemical and/or structural properties similar to a specified amino acid. In particular embodiments, an isostere or suitable isostere of an amino acid is another amino acid of the same class, wherein amino acids belong to the following classes based on the propensity of the side chain to be in contact with polar solvent like water: hydrophobic (low propensity to be in contact with water), polar or charged (energetically favorable contact with water). Illustrative charged amino acid residues include lysine (+), arginine (+), aspartate () and glutamate (). Illustrative polar amino acids include serine, threonine, asparagine, glutamine, histidine and tyrosine. Illustrative hydrophobic amino acids include alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophane, cysteine and methionine. The amino acid glycine does not have a side chain and is hard to assign to one of the above classes. However, glycine is often found at the surface of proteins, often within loops, providing high flexibility to these regions, and an isostere may have a similar feature. Proline has the opposite effect, providing rigidity to the protein structure by imposing certain torsion angles on the segment of the polypeptide chain. In certain embodiments, an isostere is a derivative of an amino acid, e.g., a derivative having one or more modified side chains as compared to the reference amino acid.

(28) The term subunit, as used herein, refers to one of a pair of polypeptides monomers that are joined to form a cyclic dimer peptide composition, e.g., at their C- and N-termini, or when referring to a C-N cyclic dimer, refers to one of a pair of C-N cyclic dimers that are joined by a linker.

(29) The terms linker, and linker moiety, as used herein, refers broadly to a chemical structure that is capable of linking together two subunits of a cyclic dimer peptide or linking two C-N cyclic monomer subunits to form a C-N cyclic dimer molecule.

(30) The term receptor, as used herein, refers to chemical groups of molecules on the cell surface or in the cell interior that have an affinity for a specific chemical group or molecule. Binding between dimer peptides and targeted integrins can provide useful diagnostic tools.

(31) The term N(alpha)Methylation, as used herein, describes the methylation of the alpha amine of an amino acid, also generally termed as an N-methylation.

(32) The term sym methylation or Arg-Me-sym, as used herein, describes the symmetrical methylation of the two nitrogens of the guanidine group of arginine. Further, the term asym methylation or Arg-Me-asym describes the methylation of a single nitrogen of the guanidine group of arginine.

(33) The term integrin-related diseases, as used herein, refer to indications that manifest as a result of integrin binding, and which may be treated through the administration of an integrin antagonist.

(34) The term pharmaceutically acceptable salt, as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response; which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by treatment of an amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.

(35) The term acylating organic compounds, as used herein refers to various compounds with carboxylic acid functionality that are used to acylate the C- and/or N-termini of a peptide molecule. Non-limiting examples of acylating organic compounds include cyclopropylacetic acid, 4-Fluorobenzoic acid, 4-fluorophenylacetic acid, 3-Phenylpropionic acid, Succinic acid, Glutaric acid, Cyclopentane carboxylic acid, glutaric acid, succinic acid, 3,3,3-trifluoropropeonic acid, 3-Fluoromethylbutyric acid, Tetrahedro-2H-Pyran-4-carboxylic acid.

(36) All peptide sequences are written according to the generally accepted convention whereby the -N-terminal amino acid residue is on the left and the -C-terminal is on the right. As used herein, the term -N-terminal refers to the free -amino group of an amino acid in a peptide, and the term -C-terminal refers to the free -carboxylic acid terminus of an amino acid in a peptide.

(37) The term amino acid or any amino acid as used here refers to any and all amino acids, including naturally occurring amino acids (e.g., alpha-amino acids), unnatural amino acids, modified amino acids, and non-natural amino acids. It includes both D- and L-amino acids. Natural amino acids include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building-blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. The non-standard, natural amino acids are pyrrolysine (found in methanogenic organisms and other eukaryotes), selenocysteine (present in many noneukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts). Unnatural or non-natural amino acids are non-proteinogenic amino acids (i.e., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 natural amino acids are known and thousands of more combinations are possible. Examples of unnatural amino acids include -amino acids (.sup.3 and .sup.2), homoamino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, alpha-methyl amino acids and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. Modified amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety not naturally present on the amino acid. Reference to corresponding D-amino acids indicates D-amino acid forms of listed amino acids.

(38) Generally, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature as set out in Nomenclature of -Amino Acids (Recommendations, 1974) Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader. Some abbreviations useful in describing the invention are defined below in the following Table 1.

(39) TABLE-US-00001 TABLE 1 Definitions and Abbreviations Abbreviation Definition DIG DiGlycolic acid (Linker) Dap Diaminopropionic acid Dab Diaminobutyric acid Pen Penicillamine Sar Sarcosine Cit Citroline Cav Cavanine Phe(4-Guanidino) 4-Guanidine-Phenylalanine NMe-Arg; N-Methyl-Arginine N(alpha)Methylation Ac- Acetyl 2-Nal 2-Napthylalanine 1-Nal 1-Napthylalanine Bip Biphenylalanine OMe-Tyr Tyrosine (O-Methyl) NMe-Lys N-Methyl-Lysine NMe-Lys (Ac) N-e-Acetyl-D-lysine 3,3-DiphenylAla 3,3 DiPhenylAlanine 3,3-DiphenylGly 3,3-DiphenylGlycine NH.sub.2 Free Amine CONH.sub.2 Amide COOH Acid Phe(4-F) 4-Fluoro-Phenylanine PEG13 Bifunctional PEG linker with 13 PolyEthylene Glycol units PEG25 Bifunctional PEG linker with 25 PolyEthylene Glycol units PEG1K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 1000 Da PEG2K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 2000 Da PEG3.4K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 3400 Da PEG5K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 5000 Da IDA -Ala-Iminodiacetic acid (Linker) IDA-Palm -Ala (Palmityl)-Iminodiacetic acid HPhe homo Phenylalanine homoPhe Ahx Aminohexanoic acid Me Methyl Triazine Amino propyl Triazine di-acid Boc-Triazine Boc-Triazine di-acid Trifluorobutyric acid Acylated with 4,4,4-Trifluorobutyric acid 2-Methly-trifluorobutyric acid acylated with 2-Methy-4,4,4-Butyric acid Trifluorpentanoic acid Acylated with 5,5,5-Trifluoropentanoic acid 1,4-Phenylenediacetic acid para-Phenylenediacetic acid (Linker) 1,3-Phenylenediacetic acid meta-Phenylenediacetic acid (Linker) DTT Dithiothreotol Nle Norleucine -HTrp or -homoTrypophane -homoTrp -HPhe or -homophenylalanine -homoPhe Phe(4-CF3) 4-Trifluoromethyl Phenylalanine -Asp -Aspartic acid embedded image -HGlu -homoglutamic acid beta-homoGlu 2-2-Indane 2-Aminoindane-2-carboxylic acid 1-1-Indane 1-Aminoindane-1-carboxylic acid Cpa CyclopentylAlanine Orn Ornithine Aoc 2-Amino octonoic acid Cba Cyclobutyl alanine HCha homocyclohexyl Alanine Cyclobutyl Cyclobutylalanine -HPhe or -homophenylalanine -homoPhe HAsp or homoAspartic acid homoAsp HLys or homoLysine homoLys HCys or homoCysteine homoCys HGlu or homoGlutamic acid homoGlu homoLeu or homoLeucine homoLeu Gla Gama-Carboxy-Glutamic acid Tic (3S-)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid embedded image Phe(4CF3) Phe(4-trifluoromethyl 3-(4-trifluoromethyl-phenyl)propionic acid Phe(2,4-diCl) (S)-Fmoc-2-amino-3-(2,4-dichlorophenyl)propionic acid Phe(3,4-diCl) (S)-Fmoc-2-amino-3-(3,4-dichlorophenyl)propionic acid Pen(O) Penicillamine sulfoxide Aic aminoindan-2-carboxylic acid Phe(2-carbomyl) L-2-carbamoylphenylalanine Phe(3-carbomyl) L-3-carbamoylphenylalanine Phe(4-carbomyl) L-4-carbomylphenylalanine Phe(4-COOH) (4-carboxy-tert-butyl)-L-phenylalanine Phe(4-OMe) (S)-4-methoxyphenylalanine Phe(4-tBu) 2-amino-3-(4-tert-butyl-phenyl)propionic acid Phe(4-F) 4-fluoro-L-phenylalanine Glu(OMe) L-glutamic acid g-methyl ester -azido-Ala-OH -azido-Alanine Aoc 8-amino-octanoic acid

(40) Reference to corresponding D-amino acids indicates D-amino acid forms of listed amino acids, e.g., at any designated amino acid position in a peptide. D-amino acid forms of naturally occurring amino acids may be indicated herein by a lower case single letter abbreviation for the amino acid. For example, K means Lysine, whereas k means D-Lysine.

(41) The present invention relates generally to cyclic dimer peptides and C-N cyclic monomers and dimers that have been shown to have integrin antagonist activity. In particular embodiments, the present invention relates to various cyclic peptide dimers comprising hetero- or homomonomer subunits that each form cyclized structures through disulfide bonds. The monomer subunits are further linked together at their C- and N-terminuses, as shown in FIG. 1. A non-limiting, representative illustration of the cyclized structure is shown in FIG. 1.

(42) In certain embodiments, a linker connects two monomeric subunits by connecting sulfur containing N-terminal amino acids at the N-terminus of each monomer subunit. In certain embodiments, the linker connects two monomeric subunits by connecting two sulfur containing C- or N-terminal amino acids. In certain embodiments C-terminal linkage can be through sulfur containing amino acids and N-terminal linkage can be through amine side chain of an amino acid by their corresponding linkers and similarly in certain embodiments the N-Terminal linkage can be through sulfur containing amino acid and the C-terminal linkage can be through amino side chain of an amino acid by their corresponding linkers. In some embodiments, the two sulfur containing amino acids are connected by a linker comprising a di-halide, an aliphatic chain, or a PEG.

(43) In particular embodiments, the present invention also relates to various C-N cyclic peptide monomers, and various C-N cyclic peptide dimers comprising hetero- or homomonomer subunits that are linked together via a linker moiety that is covalently bonded to Lys residues of the respective C-N cyclic monomer molecules. The C-N cyclic monomers and C-N cyclic monomer subunits are cyclized through C to N cyclization.

(44) In some instances, a compound of the present invention comprises a C-N cyclic monomer peptide molecule. In particular embodiments, the C-N cyclic peptide is cyclized through C to N cyclization.

(45) In certain embodiments, a C-N cyclic peptide of the present invention (or one or both C-N cyclic peptide subunits of a C-N cyclic dimer of the present invention comprise an intramolecular bond between two residues of the C-N cyclic peptide.

(46) In other instances, a compound of the present invention comprises a C-N cyclic dimer peptide construct consisting of two C-N cyclic monomer peptide molecules that are covalently linked via a linker moiety. In certain embodiments, the C-N cyclic peptide dimer is a homodimer comprising two identical C-N cyclic peptide monomer subunits. In particular embodiments, the C-N cyclic peptide dimer is a hetero dimer comprising two non-identical C-N cyclic peptide monomer subunits. In some embodiments, one or both of the C-N cyclic monomer peptide subunits of the C-N cyclic dimer comprises an intramolecular bond between two amino acid residues of the C-N cyclic monomer, e.g. an intramolecular disulfide bond, a lactam bond, an olefin bond, or a thioether bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments, neither of the two C-N cyclic monomer peptide subunits of the C-N cyclic dimer comprises an intramolecular bond, e.g. a bond between Xaa.sup.4 and Xaa.sup.10.

(47) Accordingly, the present invention provides two C-N cyclic monomer subunit peptides according to Formula (III) that are linked by a suitable linker moiety to form a C-N cyclic dimer molecule.

(48) The linker moieties of the present invention may include any structure, length, and/or size that is compatible with the teachings herein. In certain embodiments, a linker moiety is selected from the non-limiting group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. When the linker is IDA, ADA or any linker with free amine it can be acylated with acylating organic compound selected from the group consisting of 2-me-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Lauryl, Oleoyl, Lauryl, Trifluoromethyl butyric, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid, straight chain aliphatic acids with 10 to 20 carbon units, cholic acid and other bile acids. In some instances, small PEG (PEG4-PEG13), Glu, IsoGlu or Asp is used as spacer before acylations.

(49) In particular embodiments, the linker connects two monomer subunits by connecting two amino C- or N-terminal amino acids, wherein the C- or N-terminal amino acids contain an H, Me, COHN, or SS group. In some embodiments, the amino acids that contain a H, Me, COHN, or SS group are connected by a linker comprising a di-halide, an aliphatic chain, or a PEG. In certain embodiments, the linker connects two monomeric subunits by connecting C-terminal amino acids that contain a H, Me, COHN, or SS group at the C-terminus of each monomer subunit. In certain embodiments, the linker connects two monomeric subunits by connecting N-terminal amino acids that contain a H, Me, COHN, or SS group at the N-terminus of each monomer subunit. In certain embodiments, the linker connects two monomeric subunits by connecting a C-terminal amino acid that contains a H, Me, COHN, or SS group of one monomer subunit to an N-terminal amino acid that contains a H, Me, COHN, or SS group of the other monomer subunit.

(50) In certain embodiments, the linker connects two monomer subunits by connecting two sulfur containing C- or N-terminal amino acids. In some embodiments, the two sulfur containing amino acids are connected by a linker comprising a di-halide, an aliphatic chain, or a PEG. In certain embodiments, the linker connects two monomeric subunits by connecting sulfur containing C-terminal amino acids at the C-terminus of each monomer subunit. In certain embodiments, the linker connects two monomeric subunits by connecting sulfur containing N-terminal amino acids at the N-terminus of each monomer subunit. In certain embodiments, the linker connects two monomeric subunits by connecting a sulfur containing C-terminal amino acid of one monomer subunit to a sulfur-containing N-terminal amino acid of the other monomer subunit.

(51) In some embodiments, two N-terminal or C-terminal amino acids are connected by a linker comprising Homobifunctional maleimide crosslinkers, di-halide, 1,2-Bis(bromomomethyl)benzene, 1,2-Bis(chloromomethyl)benzene, 1,3-Bis(bromomomethyl)benzene, 1,3-Bis(chloromomethyl)benzene, 1,4-Bis(bromomomethyl)benzene, 1,4-Bis(chloromomethyl)benzene, 3,3-bis-bromomethyl-biphenyl, or 2,2-bis-bromomethyl-biphenyl. Particular haloacetyl crosslinkers contain an iodoacetyl or a bromoacetyl group. These homo bifunctional linkers may contain spacers comprising PEG or an aliphatic chain. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides, which may be capable of linking two monomer subunits through amine, ester, thioether, di-thio, or ether bonds.

(52) In certain embodiments, the linker is selected from the group consisting of of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides, which may be capable of linking two monomer subunits through amine, ester, thioether, di-thio, or ether bonds.

(53) When the linker is IDA, ADA or any linker with a free amine, it can be acylated, e.g. with an acylating organic compound selected from the group consisting of 2-Methyl-4,4,4,-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Oleoyl, Lauryl, Trifluoromethyl butyl, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid, straight chain aliphatic acids with 10 to 20 carbon units, cholic acid and other bile acids. In some instances, small PEG (PEG4-PEG13), Glu, IsoGlu or Asp is used as spacer before acylations. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides, which may be capable of linking two monomer subunits through amine, ester, thioether, di-thio, or ether bonds. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. It is understood that once bound to a linker or another amino acid, an amino acid residue of the peptide compound may undergo structural changes, e.g., an acid may become an amide. Reference to a particular amino acid residue encompasses the amino acid residue in any altered structural form upon binding to a linker or forming an intramolecular bond with another amino acid of the peptide compound.

(54) In certain embodiments, the linker connects two monomeric subunits by connecting two sulfur containing amino acids. In some embodiments, the two sulfur containing amino acids are connected by a linker comprising a di-halide, an aliphatic chain, or a PEG. In certain embodiments, the linker connects two monomeric subunits by connecting sulfur containing C-terminal amino acids at the C-terminus of each monomer subunit. In some embodiments, the two sulfur containing amino acids are connected by a linker comprising homobifunctional maleimide crosslinkers, di-halide, 1,2-Bis(bromomomethyl)benzene, 1,2-Bis(chloromomethyl)benzene, 1,3-Bis(bromomomethyl)benzene, 1,3-Bis(chloromomethyl)benzene, 1,4-Bis(bromomomethyl)benzene, 1,4-Bis(bromomomethyl)benzene, 3,3-bis-bromomethyl-biphenyl, or 2,2-bis-bromomethyl-biphenyl. Particular haloacetyl crosslinkers contain an iodoacetyl or a bromoacetyl group. These homo bifunctional linkers may contain spacers comprising PEG or an aliphatic chain. Non-limiting examples of suitable linker moieties are provided in Table 2.

(55) TABLE-US-00002 TABLE 2 Illustrative Linker Moieties Abbreviation Description Structure DIG DIGlycolic acid, embedded image PEG4 Bifunctional PEG linker with 4 PolyEthylene Glycol units PEG13 Bifunctional PEG linker with 13 PolyEthylene Glycol units PEG25 Bifunctional PEG linker with 25 PolyEthylene Glycol units PEG1K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 1000 Da PEG2K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 2000 Da PEG3.4K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 3400 Da PEG5K Bifunctional PEG linker with PolyEthylene Glycol Mol wt of 5000 Da IDA -Ala-Iminodiacetic acid embedded image Boc-IDA Boc--Ala-Iminodiacetic acid Ac-IDA Ac--Ala-Iminodiacetic acid 0 IDA-Palm Palmityl--Ala- Iminodiacetic acid GTA Glutaric acid PMA Pemilic acid AZA Azelaic acid DDA Dodecanedioic acid IPA Isopthalic aicd 1,3-PDA 1,3-Phenylenediacetic acid 1,4-PDA 1,4-Phenylenediacetic acid embedded image 1,2-PDA 1,2-Phenylenediacetic acid Triazine Amino propyl Triazine di-acid 0 Boc-Triazine Boc-Triazine di-acid ADA Amino diacetic acid AADA n-Acetyl amino acetic acid PEG4-Biotin PEG4-Biotin (Product number 10199, QuantaBioDesign) 1,4 BMB 1,4-Bis(halo- momethyl)benzene X = Cl, Br 1,2 BMB 1,2-Bis(lialo- momethyl)benzene embedded image XCl, Br 1,3 BMB 1,3-Bis(halo- momethyl)benzene, X = Cl, Br 1,3 BMBip 3,3-Bis-Halomethyl-Biphenyl X = Cl, Br IDA-Biotin N-Biotin--Ala- Iminodiacetic acid 2,2 BMBip 2,2-Bis-Halomethyl-Biphenyl 0 X = Cl, Br BMal Bis-Mal-dPEG n = 1 to 20

(56) One having skill in the art will appreciate that the suitable linker moieties disclosed herein are non-limiting examples, and that the present invention may include any suitable linker moiety. Thus, some embodiments of the present invention comprises a homo- or heterodimer cyclic dimer comprising two monomer subunits selected from the structures and sequences described herein, wherein the cyclic dimer peptide integrin antagonist activity. In certain embodiments, the two monomer subunits of a cyclic dimer are the same, while in other embodiments, they are different. Furthermore, some embodiments of the present invention comprises a homo- or heterodimer molecule comprises two C-N cyclic monomer subunits selected from the C-N cyclic peptide molecules described herein, wherein the C-N cyclic monomers peptides are linked by any suitable linker moiety to provide a C-N cyclic dimer molecule having integrin antagonist activity. In certain embodiments, the two C-N cyclic peptide monomer subunits of a dimer are the same, while in other embodiments, they are different.

(57) Cyclic Dimer Peptides

(58) Particular embodiments of the present invention are directed to cyclic dimer compounds, wherein the subunits are linked at both their C- and N-termini using two linker moieties. Cyclic dimers of the present invention may include homodimers and heterodimers and function as integrin antagonists. Cyclic dimers of the present invention may also include symmetrical or asymmetrical linker moieties. In a cyclic dimer, a linker may link the N-termini or C-termini of each subunit, or a linker may connect the N-terminal of one subunit to the C-terminal of the other subunit.

(59) In one aspect, the present invention relates to cyclic dimer compounds, each subunit of the dimer compound comprising the structure of Formula (I)

(60) Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.11-Xaa.sup.12-Xaa.sup.13-Xaa.sup.14 (Formula (I)), or a pharmaceutically acceptable salt thereof. In certain embodiments, one or both monomer subunit comprises an intramolecular bond, e.g., a disulfide, thioether, olefin or actam bond between Xaa.sup.4 and Xaa.sup.10.

(61) The N-terminus of a peptide monomer represented by Formula (I) can be modified by one to three suitable groups, as represented by Xaa.sup.1, Xaa.sup.2, and Xaa.sup.3. The N-terminus may further be acylated. In some instances, the N-terminus further comprises a suitable modifying group.

(62) Similarly, the C-terminus of a peptide represented by Formula (I) can be modified by a suitable group. For example, the C-terminus amino acid may be acylated. In some instances, the C-terminus further comprises a suitable modifying group, as disclosed herein.

(63) In some embodiments, Xaa.sup.1, Xaa.sup.2, and Xaa.sup.3 of Formula (I) are absent. In other embodiments, Xaa.sup.1 is absent, and Xaa.sup.2 and Xaa.sup.3 represent suitable groups for modifying the N-terminus of the peptide. Further, in some embodiments Xaa.sup.1 and Xaa.sup.2 are absent, and Xaa.sup.3 represents a single suitable group for modifying the N-terminus of the peptide.

(64) With continued reference to the general formula of Formula (I), and with respect to any of the cyclic dimer compounds or formulas described herein, in certain embodiments, any one of Xaa.sup.1-3 comprise a free amine that is selected from the group consisting of any naturally occurring amino acid, Dap, Dab, Orn, D-Orn, Lys, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-N-Me-Lys, D-Dap, D-Dab, a suitable isostere, or corresponding D-amino acid. In some embodiments, at least one of Xaa.sup.1-3 is absent. For example, in some instances Xaa.sup.1 is absent, whereby Xaa.sup.2 is the N-terminus. In other instances Xaa.sup.1 and Xaa.sup.2 are absent, whereby Xaa.sup.3 is the N-terminus. Further still, in some instances Xaa.sup.1-3 are absent, whereby Xaa.sup.4 is the N-terminus. In some embodiments, the N-terminus comprises a free amine. In particular embodiments, any one of Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, the N-terminal amino acid and/or C-terminal amino acid is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

(65) In particular embodiments, the carboxy terminus of the peptide of formula (I) (or any other cyclic peptide described herein) comprises a free amine, e.g., NH.sub.2. In particular embodiments, this free amine is present on a side chain of the C-terminal amino acid residue, e.g., Xaa.sup.11, Xaa.sup.12, Xaa.sup.13 or Xaa.sup.14. In particular embodiments, the N-terminal amino acid residue, e.g., Xaa.sup.1, Xaa.sup.2, Xaa.sup.3, or Xaa.sup.4 is modified to include a free amine. In certain embodiments, Xaa1-3 and/or Xaa11-14, particularly the amino terminal and/or carboxy terminal residue of a monomer subunit, is a sulfur-containing amino acid residue, e.g., Cys, homoCys, D-Cys, D-Pen, D-homoCys, Pen, useful for linking through a sulfhydral group.

(66) In some embodiments, Xaa.sup.4 is selected from the group consisting of Cys, Pen, Asp, Glu, homoGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, Dab, homoSer, homoSer-Cl, Allyl Gly, Allyl Pro, Allyl Bu, Amino 3-Bromo propionic acid, Amino 4-Bromo butyric acid, a modified Ser, a modified homoSer, e.g., homo Ser-Cl, a suitable isostere and corresponding D-amino acids. In certain embodiments, a disulfide or lactam or thioether or olifin bond exists between Xaa.sup.4 and Xaa.sup.10. Thus, the peptide monomers of the present invention may be cyclized through a disulfide or lactam, or thioether or olifin bond.

(67) In certain embodiments, Xaa.sup.5 is selected from the group consisting of Lys, Arg, Asn, Glu, Leu, Val, Tyr, HArg, Dap, Dab, N(alpha)Me-Arg, Arg-Me-sym, Arg-Me-asym, Phe(4-guanidino), Cit, Cav, and suitable isostere replacements.

(68) In certain embodiments, Xaa.sup.6 is selected from the group consisting of Ser, Gly, Thr, Ile, and suitable isostere replacements.

(69) In certain embodiments, Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp and a suitable isostere replacement for Asp.

(70) In certain embodiments, Xaa.sup.8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, and N-Methyl amino acids including N-Me-Thr.

(71) In certain embodiments, Xaa.sup.9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, Nle, N-Me-Leu, and suitable isostere replacements.

(72) In certain embodiments, Xaa.sup.10 is selected from the group consisting of Cys, Pen, Asp, Glu, HGlu, -Asp, -Glu, Lys, HLys, Orn, Dap, Dab, HSer, HSer-Cl, Allyl Gly, Allyl Pro, Allyl Bu, Amino 3-Bromo propionic acid, Amino 4-Bromo butyric acid a suitable isostere and corresponding D-amino acidsXaa.sup.11 is selected from the group consisting of Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Ser, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, HPhe, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, and corresponding D-amino acids and suitable isostere replacements.

(73) In certain embodiments, Xaa.sup.12 is absent, or Xaa.sup.12 is selected from the group consisting of Glu, Amide, Lys, COOH, CONH.sub.2, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, -HGlu, 2-Nal, 1-Nal, D-Asp, Bip, -HPhe, -Glu, D-Tyr, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, suitable isosteres, and corresponding D-amino acids.

(74) In certain embodiments, Xaa.sup.13 may be absent, or Xaa.sup.13 is selected from the group consisting of Gin, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-Dap, D-Dab, COOH, CONH.sub.2, suitable isosteres, and corresponding D-amino acids.

(75) Further, in some embodiments Xaa.sup.14 is absent, or Xaa.sup.14 is selected from the group consisting of natural amino acids, suitable isostere replacements, corresponding D-amino acids, and corresponding N-Methyl amino acids.

(76) For some embodiments, Xaa.sup.1-Xaa.sup.5, Xaa.sup.1-Xaa.sup.9, and Xaa.sup.11-Xaa.sup.13 are N(alpha)Methylated. Xaa.sup.5 may further be Arg-Me-sym or Arg-Me-asym, and Xaa.sup.14 may be O-Me-Tyr, N-Me-Lys(Ac), or 4-Me-Phe. In some instances, Xaa.sup.1-Xaa.sup.4, and Xaa.sup.11-Xaa.sup.14 are acylated. For example, in some instances one or more residues at positions Xaa.sup.1-Xaa.sup.4, and Xaa.sup.11-Xaa.sup.14 are acylated with an acylating organic compound selected from the group consisting of 2-Methyl-4,4,4,-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyl, cyclopentane carboxylic acid, cyclopropylacetic acid, Glutaric acid, 4-fluorobenzoic, 4-fluorophenyl acetic, and 3-Phenylpropionic acid.

(77) In some embodiments, the N-terminal residue Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3, and the C-terminal residue Xaa.sup.12, Xaa.sup.13 or Xaa.sup.14 are each modified with a suitable linker moiety to form a homo- or hetero-dimer molecule, wherein Formula (I) comprises a cyclic dimer formed from two subunits joined by suitable C- and N-terminal linkers selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. When the linker is IDA, ADA or any linker with free amine, it can be acylated with acylating organic compound selected from the group consisting of 2-me-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Lauryl, Oleoyl, Lauryl, Trifluoromethyl butyric, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid, straight chain aliphatic acids with 10 to 20 carbon units, cholic acid and other bile acids. In some instances small PEG (PEG4-PEG13), Glu, IsoGlu or Asp is used as spacer before acylations. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides, which may be capable of linking two monomer subunits through amine, ester, thioether, di-thio, or ether bonds. In some embodiments, the C- and N-terminal linkers comprise the same linker moieties, thereby forming a symmetrical cyclic dimer compound. In other embodiments, the C- and N-terminal linkers comprise different linker moieties, thereby forming an asymmetrical cyclic dimer compound.

(78) One having skill in the art will appreciate that the C- and N-terminal linker moieties disclosed herein are non-limiting examples of suitable linkers, and that the present invention may include any suitable linker moiety. Thus, the embodiments of the present invention comprises cyclic homo- or heterodimer molecules comprised of two monomer subunits selected from the peptide molecules described herein, including the accompanying sequence listing, wherein the C- and N-terminuses of the respective monomers are linked by any suitable linker moiety to provide a cyclic dimer molecule having integrin antagonist activity.

(79) The present invention further comprises a cyclic dimer peptide comprising monomer subunits according to Formula (II):
Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.14(Formula (II)),

(80) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises an intramolecular bond, e.g., a disulfide or lactam bond, between Xaa.sup.1 and Xaa.sup.7, and further wherein Formula (II) represents a monomer subunit of a cyclic dimer molecule, wherein the monomer subunits are linked to form a cyclic dimer molecule in accordance with the present invention, and wherein

(81) Xaa.sup.1 is selected from the group consisting of Cys, Pen, Asp, Glu, HGlu, -Asp, -Glu, Lys, HLys, Orn, Dap, Dab, a suitable isostere and corresponding D-amino acids;

(82) Xaa.sup.2 is selected from the group consisting of Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Met, Thr, HArg, Dap, Dab, N(alpha)Me-Arg, Arg-Me-sym, Arg-Me-asym, Phe(4-guanidino), Cit, Cav, and suitable isostere replacements;

(83) Xaa.sup.3 is selected from the group consisting of Ser, Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Glu, Leu, Val, Tyr, Trp, Met, and suitable isostere replacements;

(84) Xaa.sup.4 is selected from the group consisting of Asp, N-Me-Asp and a suitable isostere replacement for Asp;

(85) Xaa.sup.5 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, and N-Methyl amino acids including N-Me-Thr;

(86) Xaa.sup.6 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, HCha, N-Me-Leu, and suitable isostere replacements;

(87) Xaa.sup.7 is selected from the group consisting of Cys, Asp, Lys, Glu, Pen, HAsp, HGlu, HLys, Orn, -Asp, -Glu, Dap, and Dab;

(88) Xaa.sup.8 is selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and aromatic amino acids, substituted aromatic amino acids, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, HPhe, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, and corresponding D-amino acids and suitable isostere replacements;

(89) Xaa.sup.9 is absent, or Xaa.sup.9 is selected from the group consisting of Glu, Amide, Lys, COOH, CONH.sub.2, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, -HGlu, 2-Nal, 1-Nal, D-Asp, Bip, -HPhe, -Glu, D-Tyr, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, suitable isosteres, and corresponding D-amino acids;

(90) Xaa.sup.10 is absent, or Xaa.sup.10 is selected from the group consisting of Gin, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-Dap, D-Dab, COOH, CONH.sub.2, suitable isosteres, and corresponding D-amino acids; and

(91) Xaa.sup.11 is absent, or Xaa.sup.11 is selected from the group consisting of natural amino acids, suitable isostere replacements, corresponding D-amino acids, and corresponding N-Methyl amino acids.

(92) For some embodiments, at least one of Xaa.sup.2, Xaa.sup.4, Xaa.sup.5, Xaa.sup.6, Xaa.sup.8, Xaa.sup.9, Xaa.sup.10 and Xaa.sup.11 is N(alpha)Methylated. In some instances, at least one of Xaa.sup.8, Xaa.sup.9, Xaa.sup.10 and Xaa.sup.11 are acylated. For example, in some instances one or more residues at positions Xaa.sup.8-Xaa.sup.11 are acylated with an acylating organic compound selected from the group consisting of 2-Methyl-4,4,4,-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Trifluoromethyl butyl, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, and 3-Phenylpropionic acid, Succinic acid, Glutaric acid, Cyclopentane carboxylic acid, glutaric acid, succinic acid, 3,3,3-trifluoropropeonic acid, 3-Fluoromethylbutyric acid.

(93) In one aspect, the present invention provides monomer subunits of cyclic dimer peptide, each comprising a subunit of formula (I-1):
Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.11-Xaa.sup.12-Xaa.sup.13-Xaa.sup.14 (Formula (I-1))

(94) or a pharmaceutically acceptable salt thereof, wherein formula (I-1) is a optionally cyclized via a bond between Xaa.sup.4 and Xaa.sup.10 in accordance with the present invention, and wherein:

(95) Xaa.sup.1 is absent, or Xaa.sup.1 is selected from the group consisting of any naturally occurring amino acid, any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp,N-Me-Orn, N-Me-Dap, a free amine, suitable isostere, and corresponding D-amino acids;

(96) Xaa.sup.2 is absent, or Xaa.sup.2 is selected from the group consisting of any naturally occurring amino acid, any amino acid with an amine side chain, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, D-Asp, D-Glu and HomoSer, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, N-Me-D-Asp, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-N-Me-Lys, Gln, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tyr, Trp, Met, Thr a suitable isostere and corresponding D-amino acids;

(97) Xaa.sup.3 is absent, or Xaa.sup.3 is selected from the group consisting of any naturally occurring amino acid, any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Leu, Val, Tyr, Trp, Met, Ser and Thr, a suitable isostere and corresponding D-amino acids;

(98) Xaa.sup.4 is any amino acid;

(99) Xaa.sup.5 is N-Me-Arg, Arg, N-Me-Lys, Phe(4-quanidino), Phe(4-carbonylamino), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, or His; or a suitable isostere;

(100) Xaa.sup.6 is Ser, Gly, Thr, or Ile or a suitable isostere;

(101) Xaa.sup.7 is Asp, D-Asp, Asp(OMe), or N-Me-Asp or a suitable isostere;

(102) Xaa.sup.8 is Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, N-methyl amino acids, including N-Me-Thr, or a suitable isostere;

(103) Xaa.sup.9 is Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pentyl Ala, N-hexyl Ala, cyclobutyl-Ala, cyclopentyl-Ala, Leu, Nle, Cpa, Cba, homoLeu, Aoc, N-Me-Leu, or a suitable isostere;

(104) Xaa.sup.10 is any amino acid;

(105) Xaa.sup.11 is absent, or Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser, aromatic amino acids, substituted aromatic amino acids, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Ser, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, D-1-Nal, D-2-Nal, HPhe, D-Phe, D-Tyr, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, Phe(4-tBu), Phe(4-OMe), Phe(4-COOH), Phe(2-carbomyl), Phe(3-carbomyl), Phe(CF3), Phe(2,4-diCl), Phe(3,4-diCl), Aic, N-Me-Tyr, N-Me-Phe, Tic, Phe(4CF3), and corresponding D-amino acids and suitable isostere replacements;

(106) Xaa.sup.12 is absent, or selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Beta-homoGlu, Asp, D-homoGlu, Amide, Lys, COOH, CONH.sub.2, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, -HGlu, 2-Nal, 1-Nal, D-Asp, Bip, -HPhe, -Glu, D-Tyr, D-Phe, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, D-His, F(4-COOH), Tic, D-Trp, D-Leu, D-Arg, D-Thr, suitable isosteres, and corresponding D-amino acids;

(107) Xaa.sup.13 is absent or any amino acid or a suitable isostere; and

(108) Xaa.sup.14 is absent or any amino acid or a suitable isostere; or is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

(109) In certain embodiments, both the N-terminus and the C-terminus of the monomer subunit comprises a free amine, e.g., NH2. In particular embodiments, free amines are present on a side chain of the N-terminal amino acid residue, e.g., Xaa1, Xaa2, Xaa3 or Xaa4 and/or the C-terminal amino acid In particular embodiments, the N-terminal amino acid and/or C-terminal amino acid is modified to include a free amine.

(110) In particular embodiments, one or both of the N- and/or C-terminus fo the monomer subunit comprises a sulfur-containing amino acid, e.g., Cys, homoCys, D-Cys, D-Pen, D-homoCys, Pen

(111) In certain embodiments, Xaa.sup.5 is N-Me-Arg or a suitable isostere;

(112) In certain embodiments, Xaa.sup.6 is Ser or a suitable isostere;

(113) In certain embodiments, Xaa.sup.7 is Asp or a suitable isostere;

(114) In certain embodiments, Xaa.sup.8 is Thr or a suitable isostere;

(115) In certain embodiments, Xaa.sup.9 is a Leu or a suitable isostere.

(116) In certain embodiments, Xaa.sup.11 is absent, an aromatic amino acid, a substituted aromatic amino acid, or selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, and Phe(4-OMe), corresponding D-amino acids, and suitable isosteres.

(117) In certain embodiments, Xaa.sup.12 is absent, an aromatic amino acid, a substituted aromatic amino acid, an acidic amino acid, or selected from the group consisting of Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, D-Asp, Gla, beta-homoGlu, Tic, corresponding D-amino acid and suitable isosteres.

(118) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4.

(119) In certain embodiments, the monomer subunit comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a 1,2,3-triazole ring, or a thioether bond. In certain embodiments, the bond is a triazole, a selenoether, or a diselenide bond.

(120) In certain embodiments of any of the cyclic peptides described herein, Xaa.sup.4 is selected from the group consisting of: Cys, Pen, homoCys, D-Cys, D-Pen, D-homoCys, Asp, Glu, homoGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, Dap, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, hSer(Cl), 2-chloromethylbenzoic acid, Sec, corresponding D-amino acids and suitable isosteres, and Xaa.sup.10 is selected from the group consisting of: Cys, Asp, Lys, Glu, Pen, homoAsp, homoGlu, homoCys, D-Cys, D-Pen, homoLys, Orn, -Asp, -Glu, Dap, Dab, D-homoCys, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, hSer(Cl), or Sec corresponding D-amino acids and suitable isosteres.

(121) In one aspect, the present invention provides a monomer subunit of formula (I-1) wherein:

(122) Xaa.sup.4 is any amino acid;

(123) Xaa.sup.5 is selected from the group consisting of N(alpha)-Me-Arg, Arg, HArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Phe(4-guanidino), Cit, Cav, and suitable isostere replacements;

(124) Xaa.sup.6 is selected from the group consisting of Ser, Gly, and suitable isostere replacements;

(125) Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and a suitable isostere replacements;

(126) Xaa.sup.8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, and N-Methyl amino acids including N-Me-Thr;

(127) Xaa.sup.9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, N-Me-Leu, and suitable isostere replacements; and

(128) Xaa.sup.10 is any amino acid.

(129) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4.

(130) In one aspect, the present invention provides a monomer subunit of formula (I-1) wherein:

(131) Xaa.sup.4 is any amino acid;

(132) Xaa.sup.5 is selected from the group consisting of N(alpha)-Me-Arg, Arg, homoArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cit, Cav, N-Me-Lys, Phe(4-quanidino), Phe(4-carbomyl), Phe(4-NH2), N-Me-homoArg, Tyr and His, and suitable isostere replacements;

(133) Xaa.sup.6 is selected from the group consisting of Ser, Gly, Ile, and suitable isostere replacements;

(134) Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and a suitable isostere replacements;

(135) Xaa.sup.8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, homoLeu, and Nle;

(136) Xaa.sup.9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, homoLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, N-Me-Leu, and Cpa, and suitable isostere replacements; and

(137) Xaa.sup.10 is any amino acid.

(138) In one aspect, the present invention provides a monomer subunit of formula (I-1) wherein:

(139) Xaa.sup.4 is any amino acid;

(140) Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-quanidino), Phe(4-carbonylamino), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr and His;

(141) Xaa.sup.6 is Ser;

(142) Xaa.sup.7 is Asp or D-Asp;

(143) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu and Nle;

(144) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu; and

(145) Xaa.sup.10 is any amino acid residue.

(146) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.10.

(147) In one embodiment of Formula (I), herein referred to as Formula (I-A),

(148) Xaa.sup.4 is a Cys, Pen, or 5-amino-2-methyl-benzoyl moiety;

(149) Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-quanidino), Phe(4-carbonylamino), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr and His;

(150) Xaa.sup.6 is Ser, Ile, Gly, or Thre;

(151) Xaa.sup.7 is Asp or D-Asp, N-Me-Asp;

(152) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, Nle, and Val;

(153) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(154) Xaa.sup.10 is Cys or Pen; and

(155) Xaa.sup.11 is absent or selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, and Sar.

(156) In one embodiment of Formula (I), herein referred to as Formula (I-B),

(157) Xaa.sup.4 is Cys, Pen, or a 2-methylbenzoyl moiety;

(158) Xaa.sup.5 is N-Me-Arg;

(159) Xaa.sup.6 is Ser;

(160) Xaa.sup.7 is Asp or D-Asp;

(161) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu and Nle;

(162) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(163) Xaa.sup.10 is Pen; and

(164) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser

(165) In one embodiment of Formula (I), herein referred to as Formula (I-C),

(166) Xaa.sup.4 is Cys or Pen;

(167) Xaa.sup.5 is N-Me-Arg;

(168) Xaa.sup.6 is Ser;

(169) Xaa.sup.7 is Asp or D-Asp;

(170) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu and Nle;

(171) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(172) Xaa.sup.10 is Cys or Pen; and

(173) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(174) In one embodiment of Formula (I), herein referred to as Formula (I-D),

(175) Xaa.sup.4 is Pen;

(176) Xaa.sup.5 is N-Me-Arg;

(177) Xaa.sup.6 is Ser;

(178) Xaa.sup.7 is Asp or D-Asp;

(179) Xaa.sup.8 is Thr or Val;

(180) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(181) Xaa.sup.10 is Pen; and

(182) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(183) In one embodiment of Formula (I), herein referred to as Formula (I-E),

(184) Xaa.sup.4 is homoSer-Cl or a 2-methyl benzoyl moiety;

(185) Xaa.sup.5 is N-Me-Arg;

(186) Xaa.sup.6 is Ser;

(187) Xaa.sup.7 is Asp or D-Asp;

(188) Xaa.sup.8 is Thr or Val;

(189) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(190) Xaa.sup.10 is Pen, Cys, D-Cys or homoCys; and

(191) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(192) In one embodiment of Formula (I), herein referred to as Formula (I-F),

(193) Xaa.sup.4 is a 2-methylbenzoyl moiety;

(194) Xaa.sup.5 is N-Me-Arg;

(195) Xaa.sup.6 is Ser;

(196) Xaa.sup.7 is Asp or D-Asp;

(197) Xaa.sup.8 is Thr or Val;

(198) Xaa.sup.9 is Leu;

(199) Xaa.sup.10 is Pen; and

(200) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(201) In one embodiment of Formula (I), herein referred to as Formula (I-G),

(202) Xaa.sup.4 is a 2-methylbenzoyl moiety;

(203) Xaa.sup.5 is N-Me-Arg;

(204) Xaa.sup.6 is Ser;

(205) Xaa.sup.7 is Asp or D-Asp;

(206) Xaa.sup.8 is Thr or Val;

(207) Xaa.sup.9 is Leu;

(208) Xaa.sup.10 is Pen; and

(209) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Ser, Arg, Thr, Sar, and Ser.

(210) In one embodiment of Formula (I), herein referred to as Formula (I-H),

(211) Xaa.sup.4 is homoSer-Cl;

(212) Xaa.sup.5 is N-Me-Arg;

(213) Xaa.sup.6 is Ser;

(214) Xaa.sup.7 is Asp;

(215) Xaa.sup.8 is Thr or Val;

(216) Xaa.sup.9 is Leu;

(217) Xaa.sup.10 is Cys, D-Cys or homoCys; and

(218) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(219) In one embodiment of Formula (I), herein referred to as Formula (I-I),

(220) Xaa.sup.4 is a 2-methylbenzoyl moiety;

(221) Xaa.sup.5 is N-Me-Arg;

(222) Xaa.sup.6 is Ser;

(223) Xaa.sup.7 is Asp or D-Asp;

(224) Xaa.sup.8 is Thr or Val;

(225) Xaa.sup.9 is Leu;

(226) Xaa.sup.10 is Pen; and

(227) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), and homoPhe.

(228) In particular embodiments, the present invention includes cyclic peptide dimer compounds, and pharmaceutically acceptable salts thereof, e.g., acetate salts, wherein the two monomer subunits are linked via their N-termini and C-termini, having a structure of Formula (X):

(229) ##STR00032##

(230) wherein R.sub.1 and R.sub.2 are H or Me;

(231) n is any integer from 2 to 10;

(232) X is NHCO, CONH, SO, SS, C, S, N or 0;

(233) Y is a linker moiety; and

(234) Z is NHAc, absent or H.

(235) Particular embodiments are directed to a cyclic dimer with at least one cyclic monomer subunit that comprises a thioether bond between Xaa.sup.4 and Xaa.sup.10 or corresponding positions thereof, wherein Xaa.sup.4 is 2-methyl benzoyl. Certain embodiments contemplate that prior to forming the intramolecular bond, Xaa.sup.4 is a 2-chloromethyl benzoyl moiety and that the formation of the thioether bond with Xaa.sup.10, e.g. a cys or pen at Xaa.sup.10, converts the 2-chloromethyl benzoyl moiety at Xaa.sup.4 to a 2-methylbenzoyl moiety.

(236) In certain embodiments, the present invention further includes various peptide monomers that have been substituted with various modified amino acids. For example, some peptide monomers include Dab, Dap, Pen, Sar, Cit, Cav, HLeu, 2-Nal, d-1-Nal, d-2-Nal, Bip, O-Me-Tyr, -HTrp, -HPhe, Phe(4-CF3), 2-2-Indane, Phe(4-tBu), Phe(4-COOH), Bip, Phe(2,3-Cl), Phe(2,4-Cl), Phe(3-Carbomyl), Phe(4-Carbomyl), 1-1-Indane, Cyclobutyl, -HPhe, HLeu, Gla, Phe(4-NH2), HPhe, 1-Nal, Nle, homo amino acids, D-amino acids, 3-3-diPhe, cyclobutyl-Ala, HCha, Bip, -HPhe, -Glu, Phe(4-guanidino), and various N-methylated amino acids, e.g., N-methyl-Arg, including any shown in any of the accompanying tables or sequence listing or described herein. One having skill in the art will appreciate that additional substitutions may be made to achieve similar desired results, and that such substitutions are within the teaching and spirit of the present invention.

(237) In certain embodiments, one or both monomer subunits of the cyclic dimer peptide comprises an intramolecular bond, e.g., between Xaa.sup.4 and Xaa.sup.10 of Formula I or corresponding positions in other peptides. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a 1,2,3-triazole ring, or a thioether bond. In certain embodiments, the bond is a triazole, a selenoether, or a diselenide bond.

(238) With reference to compounds of Formula (I) or (I-1), in certain embodiments, a monomer subunit may have an intramolecular bond between Xaa.sup.4 and Xaa.sup.10, but understanding that the corresponding positions of other peptides, e.g., Xaa.sup.1 and Xaa.sup.7 of Formula (II), may similar be bound

(239) In certain embodiments of any of the cyclic peptides described herein, Xaa.sup.4 is selected from the group consisting of: Cys, Pen, homoCys, D-Cys, D-Pen, D-homoCys, Asp, Glu, homoGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, Dap, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, hSer(Cl), Sec, correspondingD-amino acids and suitable isosteres, and Xaa.sup.10 is selected from the group consisting of: Cys, Asp, Lys, Glu, Pen, homoAsp, homoGlu, homoCys, D-Cys, D-Pen, homoLys, Orn, -Asp, -Glu, Dap, Dab, D-homoCys, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, hSer(Cl), or Sec corresponding D-amino acids and suitable isosteres.

(240) In certain embodiments wherein the cyclic peptide comprises a disulfide bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Cys, homoCys, and Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Pen. In certain embodiments, Xaa.sup.4 is Cys or Pen. In certain embodiments, Xaa.sup.10 is Cys or Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Cys or Pen. In certain embodiments, Both Xaa.sup.4 and Xaa.sup.10 are Pen. In certain embodiments, the amino acid residue directly C-terminal to Xaa.sup.10 is an aromatic amino acid.

(241) In certain embodiments wherein the cyclic peptide comprises a lactam bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Lys, homoLys, Orn, Dap, Dab, Asp, Glu, homoGlu, D-Dap, D-Dab, D-Asp, D-Glu or D-Lys. In certain embodiments, Xaa.sup.10 is Lys, homoLys, Orn, Dap or Dab; and Xaa.sup.4 is Asp, Glu, or homoGlu. In certain embodiments, Xaa.sup.4 is Lys, homoLys, Orn, Dap or Dab; and Xaa.sup.10 is Asp, Glu, or homoGlu.

(242) In certain embodiments wherein the cyclic peptide comprises an olefin bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, and the peptide is cyclized via ring closing methasis to give the corresponding olefin/stapled peptide.

(243) In certain embodiments wherein the cyclic peptide comprises a thioether bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: a methyl benzoyl moiety, e.g., 2-methyl benzoyl moiety, Cys, N-Me-Cys, homoCys, Pen, D-Pen, D-Cys, and suitable isosteres

(244) In certain embodiments, Xaa.sup.4 is a methyl benzoyl moiety with a methyl group, e.g., capable of forming an amide bond with Xaa.sup.3, and Xaa.sup.10 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, homoCys, Pen and D-Pen. In particular embodiments, Xaa.sup.4 is a substituted methyl benzoyl moiety, and Xaa.sup.10 is Pen or Cys or hSer(Cl); In certain embodiments, Xaa.sup.4 is a substituted methyl benzoyl moue, and Xaa.sup.10 is hSer(Cl), Cys, Pen, homocys, D-Pen, D-Cys or D-homocys.

(245) In certain embodiments, Xaa.sup.4 and Xaa.sup.10 are each -azido-Ala-OH or propargylglycine, and the peptide is cyclized through a triazole ring.

(246) In certain embodiments, Xaa.sup.4 is 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, hSer(Cl), or Sec; Xaa.sup.10 is hSer(Cl) or Sec; and the intramolecular bond is a selenoether bond.

(247) In some embodiments, Xaa.sup.4 is an amino acid residue having a side chain with one or two carbons. In some instances, Xaa.sup.4 is selected from the group consisting of a modified Ser, a modified Hser (e.g., homoSer-Cl), a suitable isostere, and corresponding D-amino acids. In other instances, Xaa.sup.4 is an aliphatic acid having from one to four carbons and forming a thioether bond with Xaa.sup.10. In some instances, Xaa.sup.4 is a five- or six-membered alicyclic acid having a modified 2-methyl group that forms a thioether bond with Xaa.sup.10. In some embodiments, Xaa.sup.4 is a 2-methylbenzoyl moiety.

(248) In some embodiments, Xaa.sup.4 is selected from Cys, homoCys, Pen, and a 2-methylbenzoyl moiety. In certain embodiments, Xaa.sup.4 is selected from the group consisting of a modified Ser, a modified homoSer, a suitable isostere, and corresponding D-amino acids. In one embodiment, Xaa.sup.4 is a homoSer-Cl (before the thioether bond is formed with Xaa.sup.10 whereby the Cl is removed). In other instances, Xaa.sup.4 is an aliphatic acid having from one to four carbons and forming a thioether bond with Xaa.sup.10. In some instances, Xaa.sup.4 is a five- or six-membered alicyclic acid having a modified 2-methyl group that forms a thioether bond with Xaa.sup.10. In some instances, Xaa.sup.4 is a substituted 2-methylbenzoyl moiety. In some embodiments, the amino acid directly carboxyl to Xaa.sup.10 is an aromatic amino acid.

(249) One of skill in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain. In addition, when homoSer-Cl binds to an amino acid such as Cys or Pen via a thioether bond, the Cl moiety is released. Accordingly, as used herein, reference to an amino acid or modified amino acid, such as homoSer-Cl, present in a peptide dimer of the present invention (e.g., at position Xaa.sup.4 or position Xaa.sup.10) is meant to include the form of such amino acid or modified amino acid present in the peptide both before and after forming the intramolecular bond.

(250) Particular embodiments of the present invention are directed to cyclic dimer peptides comprising a suitable linker moiety that joins the C-termini of the peptide subunits and a suitable liner moiety that joins the N-termini of the peptide subunits. In certain embodiments, a suitable linker moiety is selected from the group consisting of DIG, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Trifluorobutyric acid, 2-Me-trifluorobutyric acid, Trifluoropentanoic acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, and Dodecanedioic acid, or a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides; wherein Formula (I) or Formula (II), or any other Formula directed to a comprises a dimer formed from two subunits joined by a suitable linker selected from the group consisting of DIG, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Trifluorobutyric acid, 2-Me-trifluorobutyric acid, Trifluoropentanoic acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, and Dodecanedioic acid bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. In particular embodiments, the linker moiety is any of those shown below.

(251) ##STR00033##

(252) Some monomer subunit sequences of the present invention are derived from the general sequences provided in Formula (I) and Formula (II). For example, the N-terminus of a decapeptide represented by Xaa.sup.4-Xaa.sup.13 of Formula (I) can be modified by one to three suitable groups, as represented by Xaa.sup.1, Xaa.sup.2, and Xaa.sup.3 of Formula (I). The N-terminus may further be acylated. The embodiments of the present invention further comprise C- and N-terminal linker moieties to facilitate linking together two monomer subunits to form various cyclic dimer molecules. Similarly, the C-terminus of the decapeptide represented by Formula (I) can be modified by a suitable group. The C-terminus may further be acylated.

(253) Some embodiments of the present invention further include a peptide homodimer or heterodimer molecule, wherein each subunit of the cyclic dimer molecule comprises an amino acid sequence represented by at least one of SEQ ID NOs: 1-146. Other embodiments comprise a peptide homodimer or heterodimer molecule, wherein each subunit of the cyclic dimer molecule comprises an amino acid sequence comprising an N(alpha)methylated arginine residue, as represented by at least one of SEQ ID NOs: 1-38, 46-52, 54-135, and 137-146. At least one embodiment comprises a peptide homodimer or heterodimer molecule, wherein at least one subunit of the cyclic dimer molecule comprises an amino acid sequence comprising an N(alpha)Methylated lysine residue, e.g., as represented by SEQ ID NO: 136.

(254) Further, some embodiments of the present invention comprise a peptide homodimer or hetereodimer molecule, wherein each subunit of the cyclic dimer molecule is cyclized through a disulfide bond, as represented by at least one of SEQ ID NOs: 1-146. In other embodiments, a peptide homo or heterodimer molecule is provided, wherein each subunit of the cyclic dimer molecule is cyclized through a lactam bond, as represented by at least one of SEQ ID NOs: 1 and 2, wherein Xaa.sup.4 and Xaa.sup.10 are selected from the group consisting of Lys, HLys, Orn, Dap, Dab, Asp, HAsp, Glu and HGlu.

(255) C-N Cylic Peptide Monomers and Dimers

(256) The present invention further includes various C-N cyclic peptide monomers and dimer subunits, as described herein.

(257) In certain embodiments, these C-N peptides comprise a non-natural amino acid, and some peptides include Dab, Dap, Pen, Sar, Cit, Cav, HLeu, 2-Nal, D-1-Nal, D-2-Nal, Bip, 0-Me-Tyr, -HTrp, -HPhe, Phe(4-CF3), 2-2-Indane, 1-1-Indane, Cyclobutyl, -HPhe, HLeu, Gla, HPhe, 1-Nal, Nle, homo amino acids, D-amino acids, 3-3-diPhe, cyclobutyl-Ala, HCha, Phe(4-NH2), Bip, -HPhe, -Glu, Phe(4-guanidino), and various N-methylated amino acids, including any shown in Table 1 or described herein. One having skill in the art will appreciate that additional substitutions may be made to achieve similar desired results, and that such substitutions are within the teaching and spirit of the present invention. In certain embodiments, any of the peptides described herein or shown in the accompanying figures further comprises one or more amino acid substititions, e.g., in certain embodiments, one or more amino acid residues is substituted with Dab, Dap, Pen, Sar, Cit, Cav, HLeu, 2-Nal, D-1-Nal, D-2-Nal, Bip, O-Me-Tyr, -HTrp, -HPhe, Phe(4-CF3), 2-2-Indane, 1-1-Indane, Cyclobutyl, -HPhe, HLeu, Gla, HPhe, 1-Nal, Nle, homo amino acids, D-amino acids, 3-3-diPhe, cyclobutyl-Ala, HCha, Phe(4-NH2), Bip, -HPhe, -Glu, Phe(4-guanidino), or an N-methylated amino acid, such as, e.g., N-methyl-Arg.

(258) In one aspect, the present invention provides a C-N cyclic monomer molecule comprising a subunit of Formula (III):
cyclo-Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10(Formula (III))

(259) or a pharmaceutically acceptable salt thereof, wherein Formula (III) is a C-N cyclic monomer that is C to N cyclized in accordance with the present invention, and wherein:

(260) Xaa.sup.1 is absent, or Xaa.sup.1 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, aromatic amino acids, substituted aromatic amino acids, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Arg, Pro, Phe, 1-Nal, 2-Nal, D-1-Nal, D-2-Nal, HPhe, D-Phe, D-Tyr, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, Phe(4-tBu), Phe(4-OMe), Phe(4-COOH), Phe(2-carbomyl), Phe(3-carbomyl), Phe(CF3), Phe(2,4-diCl), Phe(3,4-diCl), Aic, N-Me-Tyr, N-Me-Phe, Tic, Phe(4CF3), and corresponding D-amino acids and suitable isostere replacements;

(261) Xaa.sup.2 is absent, or selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Beta-homoGlu, Asp, D-homoGlu, Amide, Lys, COOH, CONH.sub.2, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, -HGlu, 2-Nal, 1-Nal, D-Asp, Bip, -HPhe, -Glu, D-Tyr, D-Phe, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, D-His, F(4-COOH), Tic, D-Trp, D-Leu, D-Arg, D-Thr, suitable isosteres, and corresponding D-amino acids;

(262) Xaa.sup.3 is absent or any amino acid or a suitable isostere;

(263) Xaa.sup.4 is any amino acid;

(264) Xaa.sup.5 is N-Me-Arg, Arg, N-Me-Lys, Phe(4-quanidino), Phe(4-carbonylamino), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Phe(4-guanidino), Cav, and His; or a suitable isostere;

(265) Xaa.sup.6 is Ser, Gly, Thr, Ile or a suitable isostere;

(266) Xaa.sup.7 is Asp, D-Asp, Asp(OMe), N-Me-Asp or a suitable isostere;

(267) Xaa.sup.8 is Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr, or a suitable isostere;

(268) Xaa.sup.9 is Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pentyl Ala, N-hexyl Ala, cyclobutyl-Ala, cyclopentyl-Ala, Leu, Nle, Cpa, Cba, homoLeu, Aoc, N-Me-Leu, or a suitable isostere; and

(269) Xaa.sup.10 is any amino acid.

(270) In certain embodiments, Xaa.sup.1 is absent, an aromatic amino acid, a substituted aromatic amino acid, or selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Phe(4-OMe), corresponding D-amino acids, and suitable isosteres.

(271) In certain embodiments, Xaa.sup.2 is absent, an aromatic amino acid, a substituted aromatic amino acid, an acidic amino acid, or selected from the group consisting of Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, D-Asp, Gla, beta-homoGlu, Tic, corresponding D-amino acid and suitable isosteres.

(272) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4.

(273) In particular embodiments, the peptide of Formula (III) is cyclized, e.g., via a covalent bond between the alpha amine of the amino terminal amino acid (the amino termini) and the alpha carboxyl of the carboxyl terminal amino acid (the carboxyl terminini) of the peptide, the amino termini and a side chain or the carboxy terminal amino acid, the carboxyl termini and a side chain of the amino terminal amino acid, or a side chain of the amino terminal amino acid and a side chain of the carboxyl terminal amino acid.

(274) In particular embodiments, the amino terminus of the peptide of Formula (III) (or any other C-N cyclic peptide described herein) comprises a free amine, e.g., NH.sub.2. In particular embodiments, this free amine is present on a side chain of the N-terminal amino acid residue, e.g., Xaa.sup.1, Xaa.sup.2, Xaa.sup.3 or Xaa.sup.4. In particular embodiments, the N-terminal amino acid residue, e.g., Xaa.sup.1, Xaa.sup.2, Xaa.sup.3, or Xaa.sup.4 is modified to include a free amine.

(275) In particular embodiments, the carboxy terminus of the peptide of Formula (III) (or any other C-N cyclic peptide described herein) comprises an OH group. In particular embodiments, the OH group is present on a side chain of the C-terminal amino acid residue, e.g., Xaa.sup.10. In particular embodiments, the C-terminal amino acid residue, e.g., Xaa.sup.10, is modified to include a hydroxy group, e.g., OH.

(276) In certain embodiments, the C-N cyclic peptide comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a 1,2,3-triazole ring, or a thioether bond. In certain embodiments, the bond is a triazole, a selenoether, or a diselenide bond.

(277) In certain embodiments of any of the C-N cyclic peptides described herein, Xaa.sup.4 is selected from the group consisting of: Cys, Pen, homoCys, D-Cys, D-Pen, D-homoCys, Asp, Glu, homoGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, Dap, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, hSer(Cl), 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, hSer(Cl), Sec, corresponding D-amino acids and suitable isosteres, and Xaa.sup.10 is selected from the group consisting of: Cys, Asp, Lys, Glu, Pen, homoAsp, homoGlu, homoCys, D-Cys, D-Pen, homoLys, Orn, -Asp, -Glu, Dap, Dab, D-homoCys, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, hSer(Cl), or Sec corresponding D-amino acids and suitable isosteres.

(278) In certain embodiments wherein the C-N cyclic peptide comprises a disulfide bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Cys, homoCys, and Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Pen. In certain embodiments, Xaa.sup.4 is Cys or Pen. In certain embodiments, Xaa.sup.10 is Cys or Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Cys or Pen. In certain embodiments, Both Xaa.sup.4 and Xaa.sup.10 are Pen. In certain embodiments, the amino acid residue directly C-terminal to Xaa.sup.10 is an aromatic amino acid.

(279) In certain embodiments wherein the C-N cyclic peptide comprises a lactam bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Lys, homoLys, Orn, Dap, Dab, Asp, Glu, homoGlu, D-Dap, D-Dab, D-Asp, D-Glu or D-Lys. In certain embodiments, Xaa.sup.10 is Lys, homoLys, Orn, Dap or Dab; and Xaa.sup.4 is Asp, Glu, or homoGlu. In certain embodiments, Xaa.sup.4 is Lys, homoLys, Orn, Dap or Dab; and Xaa.sup.10 is Asp, Glu, or homoGlu.

(280) In certain embodiments wherein the C-N cyclic peptide comprises an olefin bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, and the peptide is cyclized via ring closing methasis to give the corresponding olefin/stapled peptide.

(281) In certain embodiments wherein the C-N cyclic peptide comprises a thioether bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10are each selected from the group consisting of: a methyl benzoyl moiety, e.g., 2-methyl benzoyl moiety, Cys, N-Me-Cys, homoCys, Pen, D-Pen, D-Cys, and suitable isosteres.

(282) In certain embodiments, Xaa.sup.4 is a methyl benzoyl moiety, e.g., capable of forming an amide bond with Xaa.sup.3, and further comprising a methyl group capable of forming a thioether bond with Xaa.sup.10; and Xaa.sup.10 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, homoCys, Pen and D-Pen. In particular embodiments, Xaa.sup.4 is a methyl benzoyl moiety, and Xaa.sup.10 is Pen or Cys. In certain embodiments, Xaa.sup.4 is 2-chloromethylbenzoic acid, mercapto-propanoic acid, mercapto-butyric acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, or hSer(Cl); and Xaa.sup.10 is hSer(Cl), Cys, Pen, homocys, D-Pen, D-Cys or D-homocys.

(283) In certain embodiments, Xaa.sup.4 and Xaa.sup.10 are each -azido-Ala-OH or propargylglycine, and the peptide is cyclized through a triazole ring.

(284) In certain embodiments, Xaa.sup.4 is 2-chloromethylbenzoic acid, 2-chloro-acetic acid, 3-choro-propanoic acid, 4-chloro-butyric acid, 3-chloro-isobutyric acid, hSer(Cl), or Sec; Xaa.sup.10 is hSer(Cl) or Sec; and the intramolecular bond is a selenoether bond.

(285) In some embodiments, Xaa.sup.4 is an amino acid residue having a side chain with one or two carbons. In some instances, Xaa.sup.4 is selected from the group consisting of a modified Ser, a modified Hser (e.g., homoSer-Cl), a suitable isostere, and corresponding D-amino acids. In other instances, Xaa.sup.4 is an aliphatic acid having from one to four carbons and forming a thioether bond with Xaa.sup.10. In some instances, Xaa.sup.4 is a five- or six-membered alicyclic acid having a modified 2-methyl group that forms a thioether bond with Xaa.sup.10. In some embodiments, Xaa.sup.4 is a 2-methylbenzoyl moiety.

(286) In some embodiments, Xaa.sup.4 is selected from Cys, homoCys, Pen, and a 2-methylbenzoyl moiety. In certain embodiments, Xaa.sup.4 is selected from the group consisting of a modified Ser, a modified homoSer, a suitable isostere, and corresponding D-amino acids. In one embodiment, Xaa.sup.4 is a homoSer-Cl (before the thioether bond is formed with Xaa.sup.10 whereby the Cl is removed). In other instances, Xaa.sup.4 is an aliphatic acid having from one to four carbons and forming a thioether bond with Xaa.sup.10. In some instances, Xaa.sup.4 is a five- or six-membered alicyclic acid having a modified 2-methyl group that forms a thioether bond with Xaa.sup.10. In some instances, Xaa.sup.4 is a 2-methylbenzoyl moiety. In some embodiments, the amino acid directly carboxyl to Xaa.sup.10 is an aromatic amino acid.

(287) One of skill in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain. In addition, when homoSer-Cl binds to an amino acid such as Cys or Pen via a thioether bond, the Cl moiety is released. Accordingly, as used herein, reference to an amino acid or modified amino acid, such as homoSer-Cl, present in a peptide dimer of the present invention (e.g., at position Xaa.sup.4 or position Xaa.sup.10) is meant to include the form of such amino acid or modified amino acid present in the peptide both before and after forming the intramolecular bond.

(288) In certain embodiments, Xaa.sup.1 is absent, an aromatic amino acid, selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Phe(4-OMe), corresponding D-amino acids, and suitable isosteres;

(289) In certain embodiments, Xaa.sup.2 is absent, an aromatic amino acid, an acidic amino acid, or selected from the group consisting of Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, D-Asp, Gla, beta-homoGlu, corresponding D-amino acid and suitable isosteres;

(290) In certain embodiments, Xaa.sup.3 is absent or any amino acid or a suitable isostere;

(291) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10;

(292) In certain embodiments, Xaa.sup.5 is N-Me-Arg or a suitable isostere;

(293) In certain embodiments, Xaa.sup.6 is Ser or a suitable isostere;

(294) In certain embodiments, Xaa.sup.7 is Asp or a suitable isostere;

(295) In certain embodiments, Xaa.sup.8 is Thr or a suitable isostere;

(296) In certain embodiments, Xaa.sup.9 is a Leu or a suitable isostere; and

(297) Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4.

(298) In certain embodiments, Xaa.sup.1, Xaa.sup.2, and Xaa.sup.3 are absent. In certain embodiments, Xaa.sup.1 and Xaa.sup.2 are absent, and Xaa.sup.3 is present. In certain embodiments, Xaa.sup.1 is absent, and Xaa.sup.2 and Xaa.sup.3 are present. In certain embodiments, Xaa.sup.1 and Xaa.sup.2 are present, and Xaa.sup.3 is absent. In certain embodiments, Xaa.sup.1 is present, and Xaa.sup.2 and Xaa.sup.3 are absent. In certain embodiments, Xaa.sup.1, Xaa.sup.2, and Xaa.sup.3 are present. In certain embodiments, the N-terminal amino acid comprises a free amine capable of cyclizing with the C-terminus or C-terminal amino acid of the peptide to form a C-N cyclic peptide.

(299) In one aspect, the present invention provides a C-N cyclic monomer molecule comprising a subunit of Formula (III-2):
cyclo-(Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10)(Formula (III-2))

(300) or a pharmaceutically acceptable salt thereof, wherein Formula (III-2) is a C-N cyclic monomer that is C to N cyclized in accordance with the present invention, and wherein:

(301) Xaa.sup.1 is absent, an aromatic amino acid, a substituted aromatic amino acid, or selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, Ser, and Phe(4-OMe), corresponding D-amino acids, and suitable isosteres;

(302) Xaa.sup.2 is absent, an aromatic amino acid, a substituted aromatic amino acid, an acidic amino acid, or selected from the group consisting of Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, D-Asp, Gla, beta-homoGlu, corresponding D-amino acid and suitable isosteres;

(303) Xaa.sup.3 is absent or any amino acid or a suitable isostere;

(304) Xaa.sup.4 is any amino acid;

(305) Xaa.sup.5 is selected from the group consisting of N(alpha)-Me-Arg, Arg, HArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Phe(4-guanidino), Cit, Cav, and suitable isostere replacements;

(306) Xaa.sup.6 is selected from the group consisting of Ser, Gly, and suitable isostere replacements;

(307) Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and a suitable isostere replacements;

(308) Xaa.sup.8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, and N-Methyl amino acids including N-Me-Thr;

(309) Xaa.sup.9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, N-Me-Leu, and suitable isostere replacements; and

(310) Xaa.sup.10 is any amino acid.

(311) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.10.

(312) In one aspect, the present invention provides a C-N cyclic monomer molecule comprising a subunit of Formula (III-3):
cyclo-Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10(Formula (III-3))

(313) or a pharmaceutically acceptable salt thereof, wherein Formula (III-3) is a C-N cyclic monomer that is C to N cyclized in accordance with the present invention, and wherein:

(314) Xaa.sup.1 is absent, an aromatic amino acid, a substituted aromatic amino acid, or selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Phe(4-OMe), corresponding D-amino acids, and suitable isosteres;

(315) Xaa.sup.2 is absent, an aromatic amino acid, a substituted aromatic amino acid, an acidic amino acid, or selected from the group consisting of Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, D-Asp, Gla, beta-homoGlu, corresponding D-amino acid and suitable isosteres;

(316) Xaa.sup.3 is absent or any amino acid or a suitable isostere;

(317) Xaa.sup.4 is any amino acid;

(318) Xaa.sup.5 is selected from the group consisting of N(alpha)-Me-Arg, Arg, homoArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cit, Cav, N-Me-Lys, Phe(4-quanidino), Phe(4-carbomyl), Phe(4-NH2), N-Me-homoArg, Tyr and His, and suitable isostere replacements;

(319) Xaa.sup.6 is selected from the group consisting of Ser, Gly, Ile, and suitable isostere replacements;

(320) Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and a suitable isostere replacements;

(321) Xaa.sup.8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, homoLeu, and Nle;

(322) Xaa.sup.9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, homoLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, N-Me-Leu, and Cpa, and suitable isostere replacements;

(323) Xaa.sup.10 is any amino acid,

(324) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.10.

(325) In one aspect, the present invention provides a C-N cyclic monomer molecule comprising a subunit of Formula (III-4):
cyclo-Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10(Formula (III-4))
or a pharmaceutically acceptable salt thereof, wherein Formula (III-4) is a C-N cyclic monomer that is C to N cyclized in accordance with the present invention, and wherein:

(326) Xaa.sup.1 is absent, an aromatic amino acid, a substituted aromatic amino acid, or selected from the group consisting of Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Phe(4-OMe), corresponding D-amino acids, and suitable isosteres;

(327) Xaa.sup.2 is absent, an aromatic amino acid, a substituted aromatic amino acid, an acidic amino acid, or selected from the group consisting of Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, D-Asp, Gla, beta-homoGlu, corresponding D-amino acid and suitable isosteres;

(328) Xaa.sup.3 is absent or any amino acid or a suitable isostere;

(329) Xaa.sup.4 is any amino acid;

(330) Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-quanidino), Phe(4-carbonylamino), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr and His;

(331) Xaa.sup.6 is Ser;

(332) Xaa.sup.7 is Asp or D-Asp;

(333) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu and Nle;

(334) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(335) Xaa.sup.10 is any amino acid residue.

(336) In certain embodiments, Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10, and Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.10.

(337) In one embodiment of Formula (III), herein referred to as Formula (III-A),

(338) Xaa.sup.4 is a Cys, Pen, or 2-methyl-benzoyl moiety;

(339) Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-quanidino), Phe(4-carbonylamino), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr and His;

(340) Xaa.sup.6 is Ser, Ile, Gly, or Thre;

(341) Xaa.sup.7 is Asp or D-Asp, N-Me-Asp;

(342) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, Nle, and Val;

(343) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(344) Xaa.sup.10 is Cys or Pen; and

(345) Xaa.sup.11 is absent or selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(346) In one embodiment of Formula (III), herein referred to as Formula (III-B),

(347) Xaa.sup.4 is Cys, Pen, or a 2-methylbenzoyl moiety;

(348) Xaa.sup.5 is N-Me-Arg;

(349) Xaa.sup.6 is Ser;

(350) Xaa.sup.7 is Asp or D-Asp;

(351) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu and Nle;

(352) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(353) Xaa.sup.10 is Pen; and

(354) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser

(355) In one embodiment of Formula (III), herein referred to as Formula (III-C),

(356) Xaa.sup.4 is Cys or Pen;

(357) Xaa.sup.5 is N-Me-Arg;

(358) Xaa.sup.6 is Ser;

(359) Xaa.sup.7 is Asp or D-Asp;

(360) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu and Nle;

(361) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(362) Xaa.sup.10 is Cys or Pen; and

(363) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(364) In one embodiment of Formula (III), herein referred to as Formula (III-D),

(365) Xaa.sup.4 is Pen;

(366) Xaa.sup.5 is N-Me-Arg;

(367) Xaa.sup.6 is Ser;

(368) Xaa.sup.7 is Asp or D-Asp;

(369) Xaa.sup.8 is Thr or Val;

(370) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(371) Xaa.sup.10 is Pen; and

(372) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(373) In one embodiment of Formula (III), herein referred to as Formula (III-E),

(374) Xaa.sup.4 is homoSer-Cl or a 2-methyl benzoyl moiety;

(375) Xaa.sup.5 is N-Me-Arg;

(376) Xaa.sup.6 is Ser;

(377) Xaa.sup.7 is Asp or D-Asp;

(378) Xaa.sup.8 is Thr or Val;

(379) Xaa.sup.9 is selected from the group consisting of: Leu, Nle, Cpa, Cba, homoLeu, Aoc, and N-Me-Leu;

(380) Xaa.sup.10 is Pen, Cys, D-Cys or homoCys; and

(381) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(382) In one embodiment of Formula (III), herein referred to as Formula (III-F),

(383) Xaa.sup.4 is a 2-methylbenzoyl moiety;

(384) Xaa.sup.5 is N-Me-Arg;

(385) Xaa.sup.6 is Ser;

(386) Xaa.sup.7 is Asp or D-Asp;

(387) Xaa.sup.8 is Thr or Val;

(388) Xaa.sup.9 is Leu;

(389) Xaa.sup.10 is Pen; and

(390) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(391) In one embodiment of Formula (III), herein referred to as Formula (III-G),

(392) Xaa.sup.4 is a 2-methylbenzoyl moiety;

(393) Xaa.sup.5 is N-Me-Arg;

(394) Xaa.sup.6 is Ser;

(395) Xaa.sup.7 is Asp or D-Asp;

(396) Xaa.sup.8 is Thr or Val;

(397) Xaa.sup.9 is Leu;

(398) Xaa.sup.10 is Pen; and

(399) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(400) In one embodiment of Formula (III), herein referred to as Formula (III-H),

(401) Xaa.sup.4 is homoSer-Cl;

(402) Xaa.sup.5 is N-Me-Arg;

(403) Xaa.sup.6 is Ser;

(404) Xaa.sup.7 is Asp;

(405) Xaa.sup.8 is Thr or Val;

(406) Xaa.sup.9 is Leu;

(407) Xaa.sup.10 is Cys, D-Cys or homoCys; and

(408) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and Ser.

(409) In one embodiment of Formula (III), herein referred to as Formula (III-I),

(410) Xaa.sup.4 is a 2-methylbenzoyl moiety;

(411) Xaa.sup.5 is N-Me-Arg;

(412) Xaa.sup.6 is Ser;

(413) Xaa.sup.7 is Asp or D-Asp;

(414) Xaa.sup.8 is Thr or Val;

(415) Xaa.sup.9 is Leu;

(416) Xaa.sup.10 is Pen; and

(417) Xaa.sup.11 is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Pge(4-carbomyl), Phe(3-Carbomyl), Tyr(Me), and homoPhe.

(418) In one aspect, the present invention relates to C-N cyclic monomers and C-N cyclic dimer compounds, wherein the C-N cyclic monomer or each subunit of the dimer compound comprises the structure of Formula (IV):
cyclo-Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9(Formula (IV))

(419) wherein Formula (IV) is a C-N cyclic monomer that is C to N cyclized in accordance with the present invention, and wherein

(420) Xaa.sup.1 absent, or Xaa.sup.1 is free amind (NH.sub.2);

(421) Xaa.sup.2 is an acyl residue selected from the group consisting of any amino acid, dAla, dHis, dLys, dPhe, dLeu, dPro, dArg, and Ala, or a suitable isostere;

(422) Xaa.sup.3 is N-Me-Arg or a suitable isostere;

(423) Xaa.sup.4 or a suitable isostere is Ser;

(424) Xaa.sup.6 is Asp or a suitable isostere;

(425) Xaa.sup.7 is Thr or a suitable isostere;

(426) Xaa.sup.8 is Leu or a suitable isostere; and

(427) Xaa.sup.9 is selected from the group consisting of any amino acid, dAla, dAsp, dGlu, dLeu, dHis, and dLys, or a suitable isostere.

(428) In another aspect, the present invention provides a C-N cyclic dimer molecule comprising two C-N cyclic monomer subunit peptides according to any of the formulas are having any of the seqeunces or structures described herein, that are linked by a suitable linker moiety to form a C-N cyclic dimer molecule.

(429) In certain embodiments, the suitable linker moiety is selected from the group consisting of of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. When the linker is IDA, ADA or any linker with free amine, it can be acylated with acylating organic compound selected from the group consisting of 2-me-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Lauryl, Oleoyl, Lauryl, Trifluoromethyl butyric, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid, straight chain aliphatic acids with 10 to 20 carbon units, cholic acid and other bile acids. In some instances small PEG (PEG4-PEG13), Glu, IsoGlu or Asp is used as spacer before acylations. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides, which may be capable of linking two monomer subunits through amine, ester, thioether, di-thio, or ether bonds. In particular embodiments, the linker moiety is any of those shown below.

(430) ##STR00034##

(431) Some embodiments of the present invention provide a C-N cyclic monomer peptide molecule, wherein the C-N cyclic peptide comprises an amino acid sequence shown in any of the accompanying figures, tables, and sequence listing.

(432) Some embodiments of the present invention further include a C-N cyclic homodimer or heterodimer molecule, wherein each C-N cyclic subunit of the C-N cyclic dimer molecule comprises an amino acid sequence shown in any of the accompanying figures, tables, and

SEQUENCE LISTING

(433) In certain embodiments, the region of a C-N cyclic peptide monomer or C-N cyclic peptide dimer subunit corresponding to Xaa.sup.4-Xaa.sup.10 of Formula (I) (or which in certain embodiments includes the two amino acids capable of binding to each other at its N- and C-terminus), has a sequence shown in the peptides described in the accompanying sequence listings or tables. In particular, this region of the C-N cyclic peptide monomer or C-N cyclic peptide dimer subunit corresponds to the region of any of the peptides described in the sequence listings or tables that is defined at each end by the two amino acid residues that form an intramolecular bond with each other.

(434) Any of the specific features described hereinwith respect to one or more C-N cyclic peptides or genuses thereof may also be incorporated into any of the other C-N cyclic peptides or genuses thereof described herein.

(435) Additional Sequences of Cyclic Dimer Peptides and C-N Cyclic Monomer and Dimer Peptides

(436) In one aspect, the present invention relates to cyclic dimer compounds, or C-N cyclic peptide monomer or dimer compounds, where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises the structure

(437) Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.11-Xaa.sup.12-Xaa.sup.13-Xaa.sup.14-Xaa.sup.15 (Formula (V)), or a pharmaceutically acceptable salt thereof. The N-terminus of the nonapeptide can be modified by one to three suitable groups, as represented by Xaa.sup.1, Xaa.sup.2, and Xaa.sup.3 of Formula (V). The groups Xaa.sup.13, Xaa.sup.14, and Xaa.sup.15 of Formula (V) represent one to three groups suitable for modifying the C-terminus of the peptide. In particular embodiments, there is an intramolecular bond between Xaa.sup.4 and Xaa.sup.10.

(438) In some embodiments of Formula (V), Xaa.sup.4, Xaa.sup.2, and Xaa.sup.3 are absent. In other embodiments, Xaa.sup.1 is absent, and Xaa.sup.2 and Xaa.sup.3 represent suitable groups for modifying the N-terminus of the nonapeptide. Further, in some embodiments Xaa.sup.1 and Xaa.sup.2 are absent, and Xaa.sup.3 represents a single suitable group for modifying the N-terminus of the nonapeptide subunit.

(439) In some embodiments of Formula (V), Xaa.sup.1 is an amino acyl residue selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, suitable isosteres, and corresponding D-amino acids. In some embodiments, Xaa.sup.1 is the N-terminus and is therefore either Ac or free NH.sub.2. In at least one embodiment, Xaa.sup.1 is Ser. In other embodiments, Xaa.sup.1 is absent. Further, in at least one embodiment Xaa.sup.1 is an N-terminal linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In certain embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. Preferred Xaa.sup.1 groups for modifying the N-terminus of the compounds in the scope of the invention are free NH.sub.2, Ac, Lys, dLys.

(440) In some embodiments of Formula (V), Xaa.sup.2 is an amino acyl residue selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, and Thr. In some embodiments, Xaa.sup.2 is Thr or a corresponding D-amino acid. When Xaa.sup.1 is absent, Xaa.sup.2 is the N-terminus and is therefore either Ac, free NH.sub.2, or a suitable linker moiety. Further, in at least one embodiment Xaa.sup.2 is an N-terminal linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides In other embodiments, Xaa.sup.2 is absent. Preferred Xaa.sup.2 groups for modifying the N-terminus of the compounds in the scope of the invention are Ac, NH.sub.2, Lys, dLys and a suitable linker moiety.

(441) In some embodiments of Formula (V), Xaa.sup.3 is an amino acyl residue selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, and corresponding D-amino acids. When Xaa.sup.1 and Xaa.sup.2 are absent, Xaa.sup.3 is the N-terminus and is therefore either Ac or free NH2. Further, in at least one embodiment Xaa.sup.3 is an N-terminal linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In certain embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. In other embodiments Xaa3 is absent. Preferred Xaa.sup.3 groups for modifying the N-terminus of the compounds in the scope of the invention are Ac, Lys, dLys, NH2., and a suitable linker moiety.

(442) In some embodiments of Formula (V), Xaa.sup.4 is an amino acyl residue or analog selected from the group consisting of Cys, Pen, Asp, Glu, hGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, and Dab. When Xaa.sup.10 is Lys, homoLys, Orn, Dap or Dab, suitable groups for Xaa.sup.4 are Asp, Glu, hGlu. When Xaa.sup.10 is Asp, Glu, hGlu, suitable groups for Xaa.sup.4 are Lys, homoLys, Orn, Dap, and Dab. When Xaa.sup.4 and Xaa.sup.10 are either Cys or Pen, each subunit of the dimer is cyclized though a disulfide bond between Xaa.sup.4 and Xaa.sup.10. When Xaa.sup.4 is Lys, homoLys, Orn, Dap, or Dab, and when Xaa.sup.10 is Asp, Glu, hGlu, each subunit of the dimer is cyclized through an amide bond between Xaa.sup.4 and Xaa.sup.10. Preferably, in one embodiment Xaa.sup.4 is Cys. In another embodiment, preferably Xaa.sup.4 is Pen.

(443) In some embodiments of Formula (V), Xaa.sup.5 is an amino acyl residue or analog selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, Thr, homoArg, Dap, Dab, N-Me-Arg, Arg-(Me)sym, Arg-(me)asym, Phe(4-guanidino), Cit, Cav, and suitable isostere replacements. Preferably, Xaa.sup.5 is N-Me-Arg. In another embodiment, preferably Xaa.sup.5 is Arg.

(444) In some embodiments of Formula (V), Xaa.sup.6 is an amino acyl residue or analog selected from the group consisting of Gln, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Leu, Val, Tye, Trp, Met, and suitable isostere replacements. Preferably, Xaa.sup.6 is Gly.

(445) In some embodiments of Formula (V), Xaa.sup.7 is an amino acyl residue or analog selected from the group consisting of Asp, N-Me-Asp, and a suitable isostere replacement for Asp. Preferably, Xaa.sup.7 is Asp.

(446) In some embodiments of Formula (V), Xaa.sup.8 is an amino acyl residue or analog selected from the group consisting of Thr, Gln, Ser, Asn, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tye, Trp, Met, and N-Methyl amino acids including N-Me-Thr and a suitable isostere replacement for Thr. Preferably, Xaa.sup.8 is Thr.

(447) In some embodiments of Formula (V), Xaa.sup.9 is an amino acyl residue or analog selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Asn, Glu, Val, homoLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, N-Me-Leu, amino acids with hydrophobic side chains, and suitable isostere replacements. Preferably, Xaa.sup.9 is Leu.

(448) In some embodiments of Formula (V), Xaa.sup.10 is an amino acyl residue selected from the group consisting of Cys, Asp, Pen, Lys, homoLys, Orn, Glu, Dap, and Dab. In some embodiments, Xaa.sup.10 is selected from the group consisting of Asp, Glu, and hGlu, when Xaa.sup.4 is Lys, Dap, Dab, homoLys, or Orn. In other embodiments, Xaa.sup.10 selected from the group consisting of Lys, homoLys, Orn, Dap, or Dab when Xaa.sup.4 is Asp, Glu, or hGlu. In at least one embodiment, Xaa.sup.10 is Pen. When Xaa.sup.10 and Xaa.sup.4 are both either Cys or Pen, each subunit of the dimer is cyclized through a disulfide bond between Xaa.sup.4 and Xaa.sup.10. When Xaa.sup.10 is Asp, Glu, or hGlu, and when Xaa.sup.4 is Lys, homoLys, Orn, Dap, or Dab, each subunit of the dimer is cyclized through an amide bond between Xaa.sup.4 and Xaa.sup.10. When Xaa.sup.11 is absent and Xaa.sup.10 is the C-terminus of the subunit, Xaa.sup.10 is either COOH or amide CONH2. Preferably, in one embodiment Xaa.sup.10 is Pen. In another embodiment, Xaa.sup.10 is preferably Cys.

(449) In some embodiments of Formula (V), Xaa.sup.11 is an amino acyl residue selected from the group consisting of Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, CONH.sub.2, COOH, His, Glu, Ser, Arg, Pro, Phe, Sar, 1Nal, 2Nal, hPhe, Phe(4-F), O-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, and corresponding D-amino acids and suitable isostere replacements. When Xaa.sup.12 and Xaa.sup.13 are absent, and Xaa.sup.11 is the C-terminus of the subunit, Xaa.sup.11 is either COOH or CONH.sub.2. In at least one embodiment, Xaa.sup.11 and Xaa.sup.12 are absent. When Xaa.sup.12 and Xaa.sup.13 are absent, Xaa.sup.13 is a linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In some embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides Preferably, Xaa.sup.11 is Trp. In other embodiments Xaa.sup.11 is selected from group consisting of Lys, dLys, and N-Me-Lys.

(450) In some embodiments of Formula (V), Xaa.sup.12 is an amino acyl residue selected from the group consisting of Glu, Lys, COOH, CONH.sub.2, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, suitable isosters, and corresponding D-amino acids. When Xaa.sup.13 to Xaa.sup.15 are absent, and Xaa.sup.12 is the C-terminus of the subunit, Xaa.sup.12 is either COOH or CONH.sub.2. In some embodiments Xaa.sup.12 is absent. Preferably, Xaa.sup.12 is selected from the group consisting of Lys, dLys, and N-Me-Lys.

(451) In some embodiments of Formula (V), Xaa.sup.13 is an amino acyl residue selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tye, Trp, Met, Glu, Gla, Ser, Asn, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, COOH, CONH.sub.2, suitable isosteres, and corresponding D-amino acids. In some embodiments, when Xaa.sup.14 and Xaa.sup.15 are absent, Xaa.sup.12 is the C-terminus and Xaa.sup.13 comprises a linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. In other embodiments, the dimer molecule comprises an N-terminal linker, and therefore when Xaa.sup.14 and Xaa.sup.15 are absent, Xaa.sup.13 is the C-terminus and is therefore either COOH, or CONH.sub.2. In at least one embodiment, Xaa.sup.13 is Lys. In other embodiments, Xaa.sup.13 is absent. In at least one embodiment, Xaa.sup.14 is a C-terminal linker. Preferred Xaa.sup.13 groups for modifying the C-terminus are free NH.sub.2, COOH, CONH.sub.2 and a suitable linker moiety.

(452) In some embodiments of Formula (V), Xaa.sup.14 is an amino acyl residue selected from the group consisting of natural amino acids, COOH, CONH.sub.2, suitable isostere replacements, corresponding D-amino acids, and corresponding N-Methyl amino acids. In some embodiments, when Xaa.sup.15 is absent, Xaa.sup.13 is the C-terminus and Xaa.sup.14 comprises a linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In particular embodiments, the linker is bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. In other embodiments, the dimer molecule comprises an N-terminal linker, and therefore when Xaa.sup.15 is absent Xaa.sup.14 is the C-terminus and is therefore either COOH, or CONH.sub.2. In at least one embodiment, Xaa14 is absent. In at least one embodiment, Xaa.sup.14 is a C-terminal linker. Preferred Xaa.sup.14 groups for modifying the C-terminus are COOH, CONH.sub.2 or a suitable linker moiety.

(453) In some embodiments of Formula (V), Xaa.sup.15 is a linker moiety selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. In particular embodiments, the linker is bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides. In at least one embodiment, Xaa.sup.15 is absent. Preferably Xaa.sup.15 is DIG.

(454) Certain embodiments are directed to cyclic dimer compounds, or C-N cyclic peptide monomer or dimer compounds, where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises the structure of Formula (VI):

(455) Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.11-Xaa.sup.12-Xaa.sup.13-Xaa.sup.14 (Formula ((VI)), or a pharmaceutically acceptable salt thereof, wherein the peptide comprises a thioether bond between Xaa.sup.4 and Xaa.sup.10, and wherein:

(456) Xaa.sup.1 is absent, or Xaa.sup.1 is any amino acid;

(457) Xaa.sup.2 is absent, or Xaa.sup.2 is any amino acid;

(458) Xaa.sup.3 is absent, or Xaa.sup.3 is any amino acid;

(459) Xaa.sup.4 is an amino acid, aliphatic acid, alicyclic acid, or modified 2-methyl aromatic acid having a side chain with one or two carbons, and capable of forming a thioether bond with Xaa.sup.10;

(460) Xaa.sup.5 is selected from the group consisting of N(alpha)-Me-Arg, Arg, homoArg, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cit, Cav, N-Me-Lys, Phe(4-quanidino), Phe(4-carbamoyl amino), Phe(4-NH.sub.2), N-Me-homoArg, Tyr, His, and suitable isostere replacements;

(461) Xaa.sup.6 is selected from the group consisting of Ser, Gly, Thr, Ile, and suitable isostere replacements; wherein if Formula (VI) is directed to a dimer peptide subunit, then in some embodiments, Xaa.sup.6 is selected from the group consisting of Ser, Gly, Thr, and suitable isostere replacements;

(462) Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp, Asp(OMe), D-Asp, and suitable isostere replacements;

(463) Xaa.sup.8 is selected from the group consisting of Thr, Gln, Ser, Asp, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Asn, Glu, Val, Tyr, Trp, Leu, Met, homoLeu, Nle, and N-Methyl amino acids including N-Me-Thr;

(464) Xaa.sup.9 is selected from the group consisting of Gln, Asn, Asp, Pro, Gly, Ala, Phe, Leu, Glu, Ile, Val, HLeu, n-Butyl Ala, n-Pentyl Ala, n-Hexyl Ala, Nle, cyclobutyl-Ala, Cpa, Aoc, N-Me-Leu, and suitable isostere replacements;

(465) Xaa.sup.10 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, D-Pen, and Pen(O);

(466) Xaa.sup.11 is absent or is selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenyl-Ala, Tic, b-homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-Carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, Dihydro Trp, Ile, Leu, Arg, Thr, Sar, and aromatic amino acids, substituted aromatic amino acids, Gly, Gln, Asn, Asp, Ala, Ile, Leu, Val, Met, Thr, Lys, Trp, Tyr, His, Glu, Arg, Pro, Phe, Sar, 1-Nal, 2-Nal, D-1-Nal, D-2-Nal, HPhe, D-Phe, D-Tyr, Phe(4-F), 0-Me-Tyr, dihydro-Trp, Dap, Dab, Dab(Ac), Orn, D-Orn, N-Me-Orn, N-Me-Dap, D-Dap, D-Dab, Bip, Ala(3,3diphenyl), Biphenyl-Ala, aromatic ring substituted Phe, aromatic ring substituted Trp, aromatic ring substituted His, hetero aromatic amino acids, N-Me-Lys, N-Me-Lys(Ac), 4-Me-Phe, Phe(4-tBu), Phe(4-OMe), Phe(4-COOH), Phe(2-carbomyl), Phe(3-carbomyl), Phe(CF3), Phe(2,4-diCl), Phe(3,4-diCl), Aic, N-Me-Tyr, N-Me-Phe, Tic, Phe(4CF3), Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF3), -Me-Phe, and corresponding D-amino acids and suitable isostere replacements;

(467) Xaa.sup.12 is absent or selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Beta-homoGlu, Asp, D-homoGlu, Amide, Lys, COOH, CONH.sub.2, Gln, Pro, Gly, His, Ala, Ile, Phe, Arg, Leu, Val, Tyr, Trp, Met, Gla, Ser, Asn, D-Glu, -HGlu, 2-Nal, 1-Nal, D-Asp, Bip, -HPhe, -Glu, D-Tyr, D-Phe, D-Lys, Dap, Dab, Orn, D-Orn, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me Lys, D-Dap, D-Dab, D-His, F(4-COOH), Tic, D-Trp, D-Leu, D-Arg, D-Thr, N-Me-Glu, N-Me-Asp, alpha-H-Glu, suitable isosteres, and corresponding D-amino acids;

(468) Xaa.sup.13 is absent, or Xaa.sup.13 is any amino acid; and

(469) Xaa.sup.14 is absent or any amino acid; wherein in certain embodiments, if Formula (VI) is directed to a peptide dimer or subunit thereof, then Xaa.sup.14 is absent or selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, N-Me-Orn, Dab, N-Me-Dab, Dap, N-Me-Dap, homoLys, D-Dap, D-Dab, D-Orn, Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Cys, homoCys, COOH, CONH2, suitable isosteres, corresponding D-amino acids, and corresponding N-Methyl amino acids.

(470) In particular embodiments, there is an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In some embodiments of Formula (VI), Xaa.sup.4 is acetyl, propionyl, alpha-bromoispbutyryl, or 2-methylbenzoyl. In particular embodiments, Xaa.sup.4 is 2-methylbenzoyl. In particular embodiments, Xaa.sup.4 is 2-methylbenzoyl.

(471) In certain embodiments, a thioether peptide dimer comprises two peptide monomer subunit of Formula (VI), wherein these subunits are linked via a linker moiety through their C- or N-termini. In one embodiment, they are linked via both their C-termini.

(472) In particular embodiments, Formula (VI) is directed to a peptide monomer or a peptide dimer (or subunit thereof), and Xaa.sup.7 is selected from the group consisting of Asp, N-Me-Asp, and D-Asp.

(473) In certain embodiments of Formula (VI), Xaa.sup.13 is present and selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-N-Me-Lys, D-Dap, D-Dab, COOH, CONH.sub.2, suitable isosteres, and corresponding D-amino acids.

(474) In certain embodiments Formula (VI), Xaa.sup.14 is present. In certain embodiments, Xaa.sup.14 is selected from the group consisting of Gln, Pro, Gly, His, Ala, Ile, Phe, Lys, Arg, Leu, Val, Tyr, Trp, Met, Glu, Ser, Asn, Gla, Dap, Dab, Orn, D-Orn, D-Lys, N-Me-Orn, N-Me-Dap, N-Me-Dab, N-Me-Lys, D-N-Me-Lys, D-Dap, D-Dab, COOH, CONH.sub.2, suitable isosteres, corresponding D-amino acids, and corresponding N-Methyl amino acids. In certain embodiments, Xaa.sup.14 is D-Lys, N-Me-Lys, Dap, or Dab. In particular embodiments, Formula (I-1) is directed to a dimer peptide or subunit thereof and Xaa.sup.14 is Cys, homoCys or Pen. In certain embodiments, Xaa.sup.12 and Xaa.sup.13 are absent, and Xaa.sup.14 is D-Lys, N-Me-Lys, Dap, or Dab. In certain embodiments, Xaa.sup.13 is absent, and Xaa.sup.14 is D-Lys, N-Me-Lys, Dap, or Dab. In some embodiments, Xaa.sup.12, Xaa.sup.13 and Xaa.sup.14 are absent.

(475) Particular embodiments are directed to cyclic dimer compounds, or C-N cyclic peptide monomer or dimer compounds, where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises the structure of Formula (VII):
Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10-Xaa.sup.11-Xaa.sup.12-Xaa.sup.13-Xaa.sup.14 (Formula (VII))

(476) or a pharmaceutically acceptable salt thereof,

(477) wherein one or both subunits of the peptide dimer compound comprises a disulfide bond, a lactam bond, an olefin bond, a triazole bond, a selenoether bond, or a diselenide bond between Xaa.sup.4 and Xaa.sup.10, and further wherein Formula (VII) represents a monomer subunit of a dimer molecule, the monomer subunits are linked to form the peptide dimer compound, and wherein:

(478) Xaa.sup.1 is absent, Ac, or any amino acid;

(479) Xaa.sup.2 is absent, Ac, or any amino acid;

(480) Xaa.sup.3 is absent, Ac, or any amino acid;

(481) Xaa.sup.4 is any amino acid capable of forming a bond with Xaa.sup.10;

(482) Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidinoguanidino), Phe(4-carbomyl), Cit, Phe(4-NH.sub.2), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;

(483) Xaa.sup.6 is Ser, Ile, Gly, Thr or Ile;

(484) Xaa.sup.7 is Asp, D-Asp, Asp(OMe) or N-Me-Asp;

(485) Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr;

(486) Xaa.sup.9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pentyl Ala, N-hexyl Ala, cyclobutyl-Ala, cyclopentyl-Ala, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu;

(487) Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4;

(488) Xaa.sup.11 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, and Tic;

(489) Xaa.sup.12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, homoPhe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;
Xaa.sup.13 is absent or Pro or any amino acid; and
Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, D-Orn, Cys, homocys, Pen, D-homoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and homoSer.
In particular embodiments, Xaa.sup.14 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

(490) In particular embodiments, any one of Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

(491) In particular embodiments, the N-terminal amino acid and/or the C-terminal amino acid is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.

(492) In certain embodiments of Formula (VII), Xaa.sup.7 is Asp, D-Asp, or N-Me-Asp. In certain embodiments of Formula (VII), Xaa.sup.7 is Asp, Asp(OMe) or N-Me-Asp. In certain embodiments, Xaa.sup.7 is Asp or N-Me-Asp. In certain embodiments, Xaa.sup.7 is Asp.

(493) In certain embodiments of Formula (VII), Xaa.sup.12 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), Phe(4-tBu), Phe(4-CF3), Phe(3-CF3), Phe(CF3), homoPhe, D-Phe, Phe(2,3-di-Cl), Phe(3,4-di-Cl), N-Me-Tyr, N-Me-Phe, Phe(4-F), Phe(3-F), Phe(4-Me), Phe(3-Me), Phe(2-Me), Phe(3,4-di-Me), Phe(2,4-di-Phe), beta-MethylPhe, and biphenyl-Ala.

(494) In particular embodiments of Formula (VII), Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, homoPhe, D-1-Nal, D-2-Nal, Thr, and Val.

(495) In particular embodiments of Formula (VII), Xaa.sup.12 is selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, and corresponding D-amino acids and isosteres.

(496) In particular embodiments of Formula (VII), Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, D-Orn, Cys, homocys, Pen, D-homoCys, D-Cys, and D-Pen.

(497) In an alternative embodiment of Formula (VII), Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In another alternative embodiment of Formula (VII), Xaa.sup.14 is selected from the group consisting of: Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, of these alternatives of Formula (I), the two C-terminal amino acids of each subunit of a peptide dimer compound possess acid functionality, and they are linked through retroinverse linking by a diamine linker.

(498) In particular embodiments of Formula (VII), Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, Cys, homoCys, Pen, and D-Orn.

(499) In particular embodiments of Formula (VII), Xaa.sup.5 is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-homoArg; Xaa.sup.8 is selected from the group consisting of Leu, homoLeu, Nle and Val; Xaa.sup.9 is selected from the group consisting of: Cba, homoLeu, and Cpa; Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu); Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, and Val; or Xaa.sup.13 is Pro.

(500) In particular embodiments of Formula (VII), Xaa.sup.5 is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-homoArg. In particular embodiments of Formula (VII), Xaa.sup.8 is selected from the group consisting of Leu, homoLeu, Nle and Val. In particular embodiments of Formula (VII), Xaa.sup.9 is selected from the group consisting of: Cba, homoLeu, and Cpa. In particular embodiments of Formula (VII), Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu). In particular embodiments of Formula (VII), Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, and Val. In particular embodiments of Formula (VII), Xaa.sup.13 is Pro.

(501) In particular embodiments of Formula (VII), Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), Phe(4-tBu), Phe(4-CF3), Phe(3-CF3), Phe(CF3), homoPhe, D-Phe, Phe(2,3-di-Cl), Phe(3,4-di-Cl), N-Me-Tyr, N-Me-Phe, Phe(4-F), Phe(3-F), Phe(4-Me), Phe(3-Me), Phe(2-Me), Phe(3,4-di-Me), Phe(2,4-di-Phe), beta-MethylPhe, or biphenyl-Ala.

(502) In particular embodiments of Formula (VII), Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, homoPhe, D-1-Nal, D-2-Nal, Thr, and Val.

(503) In particular embodiments of Formula (I), Xaa.sup.7 is Asp, D-Asp or N-Me-Asp; Xaa.sup.9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, Leu, Nle, Cba, homoLeu, Aoc, and N-Me-Leu; Xaa.sup.12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, and corresponding D-amino acids and isosteres; Xaa.sup.13 is absent or Pro; and Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, and Pen.

(504) In particular embodiments of Formula (VII), Xaa.sup.7 is Asp, Asp(OMe) or N-Me-Asp.

(505) In certain embodiments of any one of Formula (VII), one or both peptide dimer subunit(s) of a cyclic peptide dimer or a C-N cyclic monomer peptide or subunit of a C-N cyclic peptide comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In particular embodiments of any one of Formulas (I) (including Formulas (I-1), (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (I-G), (I-H), (I-I)), (III) (including Formulas (III-1), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (III-I)), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), the monomer peptide or one or both peptide dimer subunit(s) comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments of any one of Formula (II), the peptide monomer or one or both peptide dimer subunit(s) comprises an intramolecular bond between Xaa.sup.1 and Xaa.sup.7. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a triazole, a selenoether, or a diselenide bond. In certain embodiments, the bond occurs directly between the two amino acid residues.

(506) In preferred embodiments of any of the cyclic dimer peptides described herein, Xaa4 and Xaa10 are both selected from Cys or Pen, and a disulfide bond links Xaa.sup.4 and Xaa.sup.10.

(507) In particular embodiments of any of Formula (VII) or Formula (VIII) or related peptides, any one or more of Xaa.sup.1, Xaa.sup.2, or Xaa.sup.3 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, this residue is located at the N-terminus of the peptide. In certain embodiments, Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is selected from the group consisting of: Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, this residue is located at the N-terminus of the peptide. In particular embodiments, the two N-terminal amino acids of each subunit of a peptide dimer compound possess acid functionality, and they are linked through retroinverse linking by a diamine linker. In particular embodiments, both subunits of a peptide dimer compound comprise an Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 selected from one of these residues, and the two subunits are linked via their respective N-termini.

(508) In one embodiment, a cyclic peptide dimer compound or cyclic peptide monomer subunit of the present invention comprises one or more peptide subunits of Formula (A):
Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa.sup.9-Xaa.sup.10 (Formula (A))
or a pharmaceutically acceptable salt thereof,
wherein
Xaa.sup.1 is Cys or Pen;
Xaa.sup.2 is N-Methyl-Arg;
Xaa.sup.3 is Ser;
Xaa.sup.4 is Asp;
Xaa.sup.5 is Thr or Val;
Xaa.sup.6 is Leu or Nle;
Xaa.sup.7 is Cys or Pen;
Xaa.sup.8 is Trp, Tic, Bip, 1-Nal, 2-Nal, Phe(4-tBu), Phe, Tyr, or Phe(4-COOH);
Xaa.sup.9 is Glu, -homoGlu, or D-Glu, and
Xaa.sup.10 is any amino acid,

(509) wherein the peptide molecule comprises a disulfide bond between Xaa.sup.1 and Xaa.sup.7.

(510) In particular embodiments of Formula (A), Xaa.sup.10 is D-Lys, N-Me-Lys or N-Me-D-Lys.

(511) In particular embodiments, Xaa.sup.1 and/or Xaa.sup.7 are Pen. In certain embodiments of Formula (A), Xaa.sup.10 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, Cys, homoCys, Pen, and D-Orn.

(512) In certain embodiments, Xaa.sup.10 or the C-terminus of the peptide comprises an NH.sub.2 or an OH.

(513) In some embodiments, the N-terminal residue and/or C-terminal residue of any of the cyclic dimer peptides described herein, e.g., cyclic dimer peptides of Formula (I) (including any of I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, and I-I,) or Formula (II), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (A), further comprises a conjugated moiety, e.g., a linker moiety, including but not limited to any of those described herein. In particular embodiments, the linker is selected from the group consisting of DIG, bifunctional PEG13, bifunctional PEG25, bifunctional PEG1K, bifunctional PEG2K, bifunctional PEG3.4K, bifunctional PEG4K, bifunctional PEG5K, IDA, IDA-Palm, IDA-Boc, IDA-Isovaleric acid, Triazine, Triazine-Boc, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, glutaric acid, Azelaic acid, Pimelic acid, Dodecanedioic acid, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da. When the linker is IDA, ADA or any linker with free amine, it can be acylated with acylating organic compound selected from the group consisting of 2-me-Trifluorobutyl, Trifluoropentyl, Acetyl, Octonyl, Butyl, Pentyl, Hexyl, Palmityl, Lauryl, Oleoyl, Lauryl, Trifluoromethyl butyric, cyclopentane carboxylic, cyclopropylacetic, 4-fluorobenzoic, 4-fluorophenyl acetic, 3-Phenylpropionic, tetrahedro-2H-pyran-4carboxylic, succinic acid, and glutaric acid, straight chain aliphatic acids with 10 to 20 carbon units, cholic acid and other bile acids. In some instances small PEG (PEG4-PEG13), Glu, IsoGlu or Asp is used as spacer before acylations. In particular embodiments, the linker is a bifunctional linker (e.g., di-acid, di-amine, dihalide, N-Hydroxy succinamine (NHS)-activated diesters, bis-maleimides, which may be capable of linking two monomer subunits through amine, ester, thioether, di-thio, or ether bonds.

(514) In particular embodiments of any of Formulas (VII) of (VIII), or related peptides including monomer subunits thereof, Xaa.sup.4 and Xaa.sup.10 are Pen, and Xaa.sup.5 is N-Me-Arg. In further embodiments of any of these formulas or peptide, Xaa.sup.4 and Xaa.sup.10 are Pen, Xaa.sup.5 is N-Me-Arg, and Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu).

(515) In certain embodiments, the amino acid directly C-terminal to Xaa10 is selected from aromatic amino acids, substituted aromatic amino acids, and Tic. In certain embodiments, the amino acid directly C-terminal to Xaa.sup.10 is an aromatic amino acid. In certain embodiments wherein the compound is a peptide dimer, Xaa.sup.14 is Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, or D-Orn. In certain embodiments, Xaa.sup.14 is Cys, homoCys, or Pen. In certain embodiments, Xaa.sup.14 or the C-terminus comprises an NH.sub.2 or an OH.

(516) In certain embodiments, a free amine in the C-terminal amino acid is capped, e.g., with an acetyl group.

(517) In certain embodiments of any of the formulas described herein, Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 can only be Ac when located at the N-terminus of the peptide compound, e.g., bound to the N-terminal amino acid of the peptide compound.

(518) In certain embodiments of Formula (VII), Xaa.sup.5 is selected from the group consisting of Cit, Phe(4-carbomylamino), and N-Me-homoArg; Xaa.sup.8 is selected from the group consisting of Leu, homoLeu, Nle and Val; Xaa.sup.9 is selected from the group consisting of Cba, homoLeu, and Cpa; Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu); Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val; or Xaa.sup.13 is Pro.

(519) In certain embodiments of Formula (VII), one or both monomer subunits of the peptide dimer compound comprises a disulfide bond, a lactam bond, an olefin bond, a 1,2,3-triazole ring, a selenoether bond, or a diselenide bond between Xaa.sup.4 and Xaa.sup.10.

(520) In certain embodiments of any one of Formula (VII) one or both peptide dimer subunit(s) comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a triazole, a selenoether, or a diselenide bond. In certain embodiments, the bond occurs directly between the two amino acid residues.

(521) In certain embodiments of Formula (VII), Xaa.sup.4 is selected from the group consisting of: Cys, Pen, homoCys, D-Cys, D-Pen, D-homoCys, Asp, Glu, homoGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, Dap, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, corresponding D-amino acids and isosteres, and Xaa.sup.10 is selected from the group consisting of: Cys, Asp, Lys, Glu, Pen, homoAsp, homoGlu, homoCys, D-Cys, D-Pen, homoLys, Orn, -Asp, -Glu, Dap, Dab, D-homoCys, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, corresponding D-amino acids and isosteres.

(522) In certain embodiments of Formula (VII), a peptide subunit comprises a disulfide bond between Xaa.sup.4 and Xaa.sup.10, and Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Cys and Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Pen.

(523) In certain embodiments of Formula (VII), Xaa.sup.10 is selected from the group consisting of Asp, homoAsp, Glu, and homoGlu, homoLys, and Xaa.sup.4 is selected from the group consisting of Lys, Dap, Dab, homoLys, Orn, and homoGlu. In certain embodiments, Xaa.sup.10 is selected from the group consisting of Lys, Dap, Dab, homoLys, Orn, and homoGlu, and Xaa.sup.4 is selected from the group consisting of Asp, homoAsp, Glu, homoGlu, and homoLys.

(524) In certain embodiments of Formula (VII), Xaa.sup.4 is selected from the group consisting of Asp, homoAsp, Glu, homoGlu, and homoLys, Xaa.sup.10 is selected from the group consisting of Lys, Dap, Dab, homoLys, Orn, and HGlu, and Xaa.sup.4 and Xaa.sup.10 are cyclized through an amide bond.

(525) In certain embodiments of Formula (VII) wherein a peptide subunit comprises an olefin bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, and the peptide is cyclized via ring closing methasis to give the corresponding olefin/stapled peptide.

(526) In certain embodiments of Formula (VII), Xaa.sup.4 is Cys, Pen, homocys, D-Pen, D-Cys or D-homoCys. In certain embodiments, Xaa.sup.10 is Cys, Pen, homoCys, D-Pen, D-Cys or D-homoCys.

(527) In certain embodiments of Formula (VII), Xaa.sup.4 and Xaa.sup.10 are each -azido-Ala-OH or propargylglycine, and the peptide dimer subunit(s) is cyclized through click chemistry leading to a triazole ring.

(528) In particular embodiments of Formula (VII), the intramolecular bond is a disulfide bond or a lactam bond.

(529) In some embodiments, the N-terminal or C-terminal amino acids of both peptide monomer subunits of a peptide dimer, e.g., Xaa.sup.1, Xaa.sup.2, Xaa.sup.3, Xaa.sup.11, Xaa.sup.12, Xaa.sup.13 or Xaa.sup.14, are modified with a suitable linker moiety to form a homo or hetero-dimer molecule, wherein Formula (VII) comprises a dimer formed from two subunits joined by a suitable C- or N-terminal linker.

(530) Certain embodiments are directed to cyclic dimer compounds or C-N cyclic peptide monomer or dimer compounds comprising the structure of Formula (VII), where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises the structure of Formula (VII) and comprises one of the following sequences: Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys);

(531) In certain embodiments subunits of the cyclic dimer compounds or C-N cyclic peptide monomer or subunits of C-N cyclic dimer compounds comprise one of the following sequences or structures: Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(-homo-Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-(-homo-Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-(-homo-Glu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu;
wherein in certain embodiments, there is a disulfide bond between the two Pen residues of the peptide or peptide monomer compound.

(532) Some embodiments are directed to cyclic dimer compounds, or C-N cyclic peptide monomer or dimer compounds, where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises the structure of Formula (VIII):
Xaa.sup.1-Xaa.sup.2-Xaa.sup.3-Xaa.sup.4-Xaa.sup.5-Xaa.sup.6-Xaa.sup.7-Xaa.sup.8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14 (Formula (VIII))
or a pharmaceutically acceptable salt thereof,
wherein the peptide compound comprises a disulfide bond, a lactam bond, an olefin bond, a triazole bond, a selenoether bond, or a diselenide bond between Xaa.sup.4 and Xaa.sup.10, wherein:
Xaa.sup.1 is absent, Ac, or any amino acid;
Xaa.sup.2 is absent, Ac, or any amino acid;
Xaa.sup.3 is absent, Ac, or any amino acid;
Xaa.sup.4 is any amino acid capable of forming a bond with Xaa;
Xaa.sup.5 is selected from the group consisting of: N-Me-Arg, Arg, N-Me-Lys, Phe(4-guanidino), Phe(4-carbomyl), Cit, Phe(4-NH2), N-Me-homoArg, homoArg, Tyr, Dap, Dab, Arg-Me-sym, Arg-Me-asym, Cav, and His;
Xaa.sup.6 is Ser, Gly, Thr, or Ile;
Xaa.sup.7 is Asp, D-Asp, Asp(OMe), or N-Me-Asp;
Xaa.sup.8 is selected from the group consisting of: Thr, Val, Ile, Leu, homoLeu, homoLeu, Gln, Ser, Asp, Pro, Gly, His, Ala, Phe, Lys, Arg, Asn, Glu, Tyr, Trp, Met, Nle, and N-methyl amino acids, including N-Me-Thr;
Xaa.sup.9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pentyl Ala, N-hexyl Ala, cyclobutyl-Ala, cyclopentyl-Ala, Leu, Nle, Cba, homoLeu, Cpa, Aoc, and N-Me-Leu;
Xaa.sup.10 is any amino acid capable of forming a bond with Xaa.sup.4;
Xaa.sup.11 is absent or selected from the group consisting of: Trp, Phe, 2-Nal, 1-Nal, Tyr, His, Phe(4-F), Phe(4-CF3), Phe(4-CH3), Phe(4-tBu), Bip, Phe(4-COOH), Gly, 3,3-DiPhenylGly, 3,3-DiPhenylAla, Tic, -homoTrp, D-1-Nal, D-2-Nal, Phe(2,4-diCl), Phe(3,4-diCl), Phe(4-carbomyl), Phe(3-carbomyl), Phe(2-carbomyl), Tyr(Me), homoPhe, N-Me-Phe, N-Me-Tyr, Ser, Sar, 2,3-dihydro-Trp, Ile, Leu, Arg, Thr, aromatic amino acids, substituted aromatic amino acids, and Tic;
Xaa.sup.12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, homoPhe, D-1-Nal, D-2-Nal, Thr, and Val, and corresponding D-amino acids and isosteres;
Xaa.sup.13 is absent, Pro, or any amino acid; and
Xaa.sup.14 is any amino acid.
In particular embodiments, any one of Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-AspIn certain embodiments of Formula (VIII), Xaa.sup.7 is Asp, Asp(OMe), or N-Me-Asp.
In particular embodiments, Xaa.sup.11 is selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-AspIn certain embodiments of Formula (VIII), Xaa.sup.12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, and corresponding D-amino acids and isosteres.
In particular embodiments, the N-terminal amino acid and/or the C-terminal amino acid are selected from any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp.
In certain embodiments of Formula (VIII), Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), Phe(4-tBu), Phe(4-CF3), Phe(3-CF3), Phe(CF3), homoPhe, D-Phe, Phe(2,3-di-Cl), Phe(3,4-di-Cl), N-Me-Tyr, N-Me-Phe, Phe(4-F), Phe(3-F), Phe(4-Me), Phe(3-Me), Phe(2-Me), Phe(3,4-di-Me), Phe(2,4-di-Phe), beta-MethylPhe, and biphenyl-Ala.

(533) In particular embodiments of Formula (VIII), Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), Asn, D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-Tyr, D-Lys, D-Ile, D-His, N-Me-Glu, N-Me-Asp, alpha-homoGlu, Biphenyl-Gly, Biphenyl-Ala, homoPhe, D-1-Nal, D-2-Nal, Thr, and Val.

(534) In particular embodiments of Formula (VIII), Xaa.sup.12 is selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, and corresponding D-amino acids and isosteres.

(535) In certain embodiments of Formula (VIII), Xaa.sup.2 is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-homoArg; Xaa.sup.5 is selected from the group consisting of Leu, homoLeu, Nle and Val; Xaa.sup.6 is selected from the group consisting of: Cba, homoLeu, and Cpa; Xaa.sup.8 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu); Xaa.sup.9 is selected from the group consisting of Aic, Gin, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, Val; or Xaa.sup.10 is Pro. In particular embodiments, the intramolecular bond is a disulfide bond.

(536) In certain embodiments, the amino acid directly C-terminal to Xaa.sup.10 is selected from aromatic amino acids, substituted aromatic amino acids, and Tic. In certain embodiments, the amino acid directly C-terminal to Xaa.sup.10 is an aromatic amino acid.

(537) In certain embodiments, Xaa.sup.14 or the C-terminal amino acid does not comprise a free amine.

(538) In certain embodiments, Xaa.sup.14 is Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, or D-Orn.

(539) In certain embodiments, Xaa.sup.14 or the C-terminus comprises an NH.sub.2 or an OH.

(540) In certain embodiments, a free amine in the C-terminal amino acid is capped, e.g., with an acetyl group.

(541) In certain embodiments of Formula (VIII), a C-N peptide monomer or one or more subunit(s) of a cyclic peptide dimer or C-N cyclic peptide dimer comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a triazole, a selenoether, or a diselenide bond. In certain embodiments, the bond occurs directly between the two amino acid residues.

(542) In certain embodiments of Formula (VIII), Xaa.sup.4 is selected from the group consisting of: Cys, Pen, homoCys, D-Cys, D-Pen, D-homoCys, Asp, Glu, homoGlu, -Asp, -Glu, Lys, homoLys, Orn, Dap, Dap, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, corresponding D-amino acids and suitable isosteres, and Xaa.sup.10 is selected from the group consisting of: Cys, Asp, Lys, Glu, Pen, homoAsp, homoGlu, D-Cys, D-Pen, homoLys, Orn, -Asp, -Glu, Dap, Dab, D-homoCys, 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, corresponding D-amino acids and suitable isosteres.

(543) In certain embodiments wherein the cyclic peptide comprises a disulfide bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Cys, and Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Pen.

(544) In certain embodiments wherein the cyclic peptide comprises a lactam bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Lys, homoLys, Orn, Dap, Dab, Asp, Glu, homoGlu, D-Dap, D-Dab, D-Asp, D-Glu or D-Lys. In certain embodiments, Xaa.sup.10 is Lys, homoLys, Orn, Dap or Dab; and Xaa.sup.4 is Asp, Glu, or homoGlu. In certain embodiments, Xaa.sup.4 is Lys, homoLys, Orn, Dap or Dab; and Xaa.sup.10 is Asp, Glu, or homoGlu.

(545) In certain embodiments wherein the cyclic peptide comprises a lactam bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.10 is selected from the group consisting of Asp, HAsp, Glu, and HGlu, HLys, and Xaa.sup.4 is selected from the group consisting of Lys, Dap, Dab, HLys, Orn, and HGl. In certain embodiments, Xaa.sup.10 is selected from the group consisting of Lys, Dap, Dab, HLys, Orn, and HGlu, and Xaa.sup.4 is selected from the group consisting of Asp, HAsp, Glu, HGlu, and HLys.

(546) In certain embodiments, Xaa.sup.4 is selected from the group consisting of Asp, HAsp, Glu, HGlu, and Hlys, Xaa.sup.10 is selected from the group consisting of Lys, Dap, Dab, HLys, Orn, and HGlu, and Xaa.sup.4 and Xaa.sup.10 are cyclized through an amide bond.

(547) In certain embodiments of Formula (VIII) wherein the cyclic peptide comprises an olefin bond between Xaa.sup.4 and Xaa.sup.10, Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: 2-allylglycine, 2-(3-butenyl)glycine, 2-(4-pentenyl)glycine, or 2-(5-hexenyl)glycine, and the peptide is cyclized via ring closing methasis to give the corresponding olefin/stapled peptide.

(548) In certain embodiments of Formula (VIII), Xaa.sup.4 is Cys, Pen, or homocys. In certain embodiments, Xaa.sup.4 and Xaa.sup.10 are each -azido-Ala-OH or propargylglycine, and the peptide is cyclized through click chemistry leading to a triazole ring. In particular embodiments, the intramolecular bond is a disulfide bond or a lactam bond.

(549) In certain embodiments of Formula (VIII), Xaa.sup.7 is Asp, D-Asp, or N-Me-Asp. In certain embodiments of Formula (VIII), Xaa.sup.7 is Asp, Asp(OMe) or N-Me-Asp. In certain embodiments, Xaa.sup.7 is Asp or N-Me-Asp. In certain embodiments, Xaa.sup.7 is Asp.

(550) In particular embodiments of Formula (VIII), Xaa.sup.12 is selected from the group consisting of aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, and corresponding D-amino acids and isosteres.

(551) In particular embodiments of Formula (VIII), Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, D-Orn, Cys, homoCys, Pen, D-homoCys, D-Cys, and D-Pen.

(552) In particular embodiments of Formula (VIII), Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, Cys, homoCys, Pen, and D-Orn.

(553) In an alternative embodiment of Formula (VIII), Xaa14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, Pen, D-HomoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and HomoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In another alternative embodiment of Formula (VIII), Xaa.sup.14 is selected from the group.sub.=consisting of: Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, of these alternatives of Formula (VIII), the two C-terminal amino acids of each subunit of a peptide dimer compound possess acid functionality, and they are linked through retroinverse linking by a diamine linker.

(554) In particular embodiments of Formula (VIII), Xaa.sup.5 is selected from the group consisting of Cit, Phe(4-carbomyl), and N-Me-homoArg. In particular embodiments of Formula (VIII), Xaa.sup.8 is selected from the group consisting of Leu, homoLeu, Nle and Val. In particular embodiments of Formula (VIII), Xaa.sup.9 is selected from the group consisting of: Cba, homoLeu, and Cpa. In particular embodiments of Formula (VIII), Xaa.sup.11 is selected from the group consisting of Tic, Phe(2-carbomyl), Phe(3-carbomyl), Phe(4-COOH), Phe(4-OMe), and Phe(4-tBu). In particular embodiments of Formula (VIII), Xaa.sup.12 is selected from the group consisting of Aic, Gln, Cit, Glu(OMe), D-His, Tic, Phe(3-COOH), D-Arg, Bip, D-Trp, Phe, D-Phe, D-Val, D-Thr, D-1-Nal, D-2-Nal, Thr, and Val. In particular embodiments of Formula (VIII), Xaa.sup.13 is Pro.

(555) In particular embodiments of Formula (I), Xaa.sup.7 is Asp, D-Asp or N-Me-Asp; Xaa.sup.9 is selected from the group consisting of: Gln, Ser, Asp, Pro, Gly, Ala, Phe, Glu, Ile, Val, N-butyl Ala, N-pental Ala, N-hexyl Ala, cyclobutyl Ala, Leu, Nle, Cba, homoLeu, Aoc, and N-Me-Leu; Xaa.sup.12 is absent or selected from the group consisting of: aromatic amino acids, substituted aromatic amino acids, Glu, D-Glu, homoGlu, Asp, D-Asp, D-homoGlu, Gla, beta-homoGlu, Tic, and corresponding D-amino acids and isosteres; Xaa.sup.13 is absent or Pro; and Xaa.sup.14 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, HomoLys, D-Dap, D-Dab, D-Orn, Cys, HomoCys, and Pen.

(556) In certain embodiments of Formula (VIII), a C-N peptide monomer or one or more subunit(s) of a cyclic peptide dimer or C-N cyclic peptide dimer comprises an intramolecular bond between Xaa.sup.4 and Xaa.sup.10. In certain embodiments, the bond is a disulfide bond, a lactam bond, an olefin bond, a triazole, a selenoether, or a diselenide bond. In certain embodiments, the bond occurs directly between the two amino acid residues.

(557) In certain embodiments of Formula (VIII), a peptide comprises a disulfide bond between Xaa.sup.4 and Xaa.sup.10, and Xaa.sup.4 and Xaa.sup.10 are each selected from the group consisting of: Cys and Pen. In certain embodiments, both Xaa.sup.4 and Xaa.sup.10 are Pen.

(558) In certain embodiments of Formula (VIII), Xaa.sup.10 is selected from the group consisting of Asp, homoAsp, Glu, and homoGlu, homoLys, and Xaa.sup.4 is selected from the group consisting of Lys, Dap, Dab, homoLys, Orn, and homoGlu. In certain embodiments, Xaa.sup.10 is selected from the group consisting of Lys, Dap, Dab, homoLys, Orn, and homoGlu, and Xaa.sup.4 is selected from the group consisting of Asp, homoAsp, Glu, homoGlu, and homoLys.

(559) In certain embodiments of Formula (VIII), Xaa.sup.4 is selected from the group consisting of Asp, homoAsp, Glu, homoGlu, and homoLys, Xaa.sup.10 is selected from the group consisting of Lys, Dap, Dab, homoLys, Orn, and HGlu, and Xaa.sup.4 and Xaa.sup.10 are cyclized through an amide bond.

(560) In particular embodiments of Formula (VIII), intramolecular bond is a disulfide bond or a lactam bond.

(561) In certain embodiments of Formula (VIII), Xaa.sup.4 is Cys, Pen, homoCys, D-Pen, D-Cys or D homoCys. In certain embodiments, Xaa10 is Cys, Pen, homoCys, D-Pen, D-Cys or D-homoCys. In certain embodiments of Formula (VIII), Xaa.sup.4 and Xaa.sup.10 are each -azido-Ala-OH or propargylglycine, and the peptide dimer subunit(s) is cyclized through click chemistry leading to a triazole ring.

(562) Certain embodiments are directed to cyclic dimer compounds or C-N cyclic peptide monomer or dimer compounds comprising the structure of formula (VIII), where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises the structure of Formula (VIII) and comprises one of the following sequences:

(563) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(Glu)-(D-Lys);

(564) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-COOH))-(-homo-Glu)-(D-Lys);

(565) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu-(D-Lys);

(566) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-(-homo-Glu)-(D-Lys);

(567) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe(4-tBu))-Glu-(N-Me-Lys);

(568) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-Glu-(D-Lys);

(569) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Bip-(-homo-Glu)-(D-Lys);

(570) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys);

(571) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu)-(D-Lys);

(572) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys);

(573) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(D-Lys);

(574) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys);

(575) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys);

(576) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(D-Lys);

(577) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(N-Me-Lys);

(578) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(N-Me-Lys);

(579) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(N-Me-Lys);

(580) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys);

(581) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(N-Me-Lys);

(582) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys);

(583) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys);

(584) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys);

(585) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu)-(D-Lys);

(586) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys);

(587) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(D-Lys);

(588) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys);

(589) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys);

(590) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(D-Lys);

(591) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(N-Me-Lys);

(592) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(N-Me-Lys);

(593) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(N-Me-Lys);

(594) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys);

(595) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(N-Me-Lys);

(596) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); or

(597) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys),

(598) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu);

(599) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu);

(600) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu;

(601) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu);

(602) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu);

(603) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu;

(604) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu);

(605) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu);

(606) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu);

(607) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu);

(608) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu);

(609) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu);

(610) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); or

(611) Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu.

(612) In certain particular embodiments, the present invention includes C-N cyclic monomers and dimer compounds, or cyclic dimer peptide dimer compounds, comprising one or two monomer subunits comprising one of the following amino acid sequences, wherein the monomer subunits of the peptide dimer are linked via their C-terminus: Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(D-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu)-(N-Me-Lys); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu)-(D-Lys); or Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu-(N-Me-D-Lys),
and wherein there is a disulfide bond between the two Pen residues of the monomer subunits. In certain particular embodiments, the present invention includes C-N cyclic peptide compounds, or cyclic peptide dimer compounds comprising one or two monomer subunits comprising one of the following amino acid sequences, wherein the monomer subunits of the peptide dimer are linked via their N-termini or their C-termini: Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-(Phe-(4-COOH)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-Glu; Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-2-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-1-Nal-(-homoGlu); Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-(-homoGlu); or Pen-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Trp-Glu,
wherein a disulfide bond links the Pen residues within a monomer dimer subunit.

(613) Certain embodiments are directed to cyclic dimer compounds, or C-N cyclic peptide monomer or dimer compounds, where each C-N cyclic monomer or each subunit of the cylic dimer compound or C-N cyclic dimer compound comprises a sequence listed in Table 3.

(614) TABLE-US-00003 TABLE 3 Illustrative peptide sequences SEQ ID NO: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 147 Ac C R S D T L C G E NH.sub.2 148 Ac C R S D T L C NH.sub.2 149 Ac C R S D T L C G E K NH.sub.2 150 Ac C R S D T L C G E K NH.sub.2 151 Ac C NMeR S D T L C G E NH.sub.2 152 Ac C NMeR S D T L C G E K OH 153 Ac C NMeR S D T L C K OH 154 Ac C NMeR S D T L C G E K OH 155 Ac C NMeR S D T L Pen k NH.sub.2 156 NH.sub.2 C NMeR S D T L C NH.sub.2 157 Ac C NMeR S D T L Pen k NH.sub.2 158 Ac C NMeR S D T L Pen W k NH.sub.2 159 Ac C NMeR S D T L Pen E k NH.sub.2 160 Ac Pen R S D T L C k NH.sub.2 161 Ac Pen R S D T L C k NH.sub.2 162 Ac Pen NMeR S D T L Pen W k NH.sub.2 163 Ac Pen NMeR S D T L Pen W k NH.sub.2 164 Ac Pen NMeR S D T L Pen W E k NH.sub.2 165 Ac Pen NMeR S D T L Pen 2-Nal E k NH.sub.2 166 Ac Pen NMeR S D T L Pen W e k NH.sub.2 167 Ac Pen NMeR S D T L Pen 2-Nal E k NH.sub.2 168 Ac Pen NMeR S D T L Pen W e k OH 169 Ac Pen NMeR S D T L Pen W b-h-E k NH.sub.2 170 Ac Pen NMeR S D T L Pen W E NMe-k NH.sub.2 171 Ac Pen NMeR S D T L Pen W E NMeK NH.sub.2 172 2- NMeR S D T L Pen F e k NH.sub.2 MB 173 Ac Pen NMeR S D T L Pen W E k NH.sub.2 174 Ac Pen NMeR S D T L Pen W e k NH.sub.2 175 2- NMeR S D T L C Tic e k NH.sub.2 MB 176 2- NMeR S D T L Pen 2-Nal e k NH.sub.2 MB 177 Ac Pen NMeR S D T L Pen W E k OH 178 2- NMeR S D T L Pen F e k OH MB 179 Ac Pen NMeR S D T L Pen F(4- b-H-E k NH.sub.2 tBu)

(615) Tables 4-6 are tables of sequences of illustrative dimer subunits of cyclic dimers according to the present invention. Any of these peptides may be dimerized at the N- and C-terminus as described herein. The sequences of tables 4-6 are also sequences of illustrative peptide monomer or dimer subunits of C-N cyclic peptides.

(616) TABLE-US-00004 TABLE 4 Illustrative Peptide Sequences SEQ ID NO: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 180 (C NMeR S D T L C Dab OH Oct) 181 (NH2 C NMeR S D T L Pen 2Nal k OH) 182 (NH2 R C NMeR S D T L Pen 1Nal K OH) 183 (NH2 E C NMeR S D T L Pen 1Nal K OH) 184 (NH2 C NMeR S D T L C G E Dab OH) 185 (NH2 C NMeR S D T L C G E k OH) 186 (NH2 C NMeR S D T L C G E K OH) 187 (NH2 R C NMeR S D T L Pen W K OH) 188 (NH2 C NMeR S D T L C G E K OH) 189 (NH2 R C NMeR S D T L Pen Y K OH) 190 (NH2 C NMeR S D T L Pen H K OH) 191 (NH2 C NMeR S D T L Pen W k OH) 192 (NH2 C NMeR S D T L C G E k OH) 193 (NH2 Pen R S D T L Pen Y k OH) 194 (NH2 C NMeR S D T L Pen k OH) 195 (NH2 Pen R S D T L Pen W k OH) 196 (C NMeR S D T L C Dab OH) 197 (NH2 C NMeR S D T L Pen Hphe k OH) 198 (NH2 C NMeR S D T L Pen Bip k OH) 199 (S C NMeR S D T L Pen OH) 200 (NH2 C NMeR S D T L Pen Phe k OH) (4-F) 201 (NH2 C NMeR S D T L C G E k OH) 202 (NH2 E C NMeR S D T L Pen Y K OH) 203 (NH2 C NMeR S D T L C G E Dab OH) 204 (NH2 C NMeR S D T L Pen k OH) 205 (NH2 C NMeR S D T L Pen W k OH) 206 (Y C NMeR S D T L Pen OH) 207 (NH2 C NMeR S D T L Pen 1Nal k OH) 208 (C NMeR S D T L C Dab OH (NH) 209 (L C NMeR S D T L Pen OH) 210 (NH2 E C NMeR S D T L Pen W K OH) 211 (NH2 K L C NMeR S D T L Pen OH) 212 (NH2 C NMeR S D T L C G E K OH) 213 (NH2 C NMeR S D T L Pen k OH) 214 (NH2 C NMeR S D T L Pen W K OH) 215 (NH2 C NMeR S D T L Pen F k OH) 216 (H C NMeR S D T L Pen OH) 217 (C NMeR S D T L C Dab OH) (NH) 218 (NH2 K E C NMeR S D T L Pen OH) 219 (NH2 C NMeR S D T L Pen W k OH) 220 (NH2 C NMeR S D T L Pen W k OH) 221 (NH2 C NMeR S D T L C G E K OH) 222 (NH2 C NMeR S D T L C G E Dab OH) 223 (NH2 C NMeR S D T L Pen f k OH) 224 (C NMeR S D T L C Dab OH 225 (NH2 K P C NMeR S D T L Pen OH) 226 (NH2 C NMeR S D T L C G E K OH) 227 (NH2 C NMeR S D T L Pen H k OH) 228 (NH2 K S C NMeR S D T L Pen OH) 229 (NH2 K N C NMeR S D T L Pen OH) 230 (NH2 C NMeR S D T L C G E k OH) 231 (NH2 K Y C NMeR S D T L Pen OH) 232 (NH2 C NMeR S D T L Pen Y K OH) 233 (NH2 C NMeR S D T L C G E Dab OH) 234 (NH2 C NMeR S D T L Pen W k OH) 235 (NH2 C NMeR S D T L Pen P k OH) 236 (NH2 C NMeR S D T L Pen W k OH) 237 (NH2 Pen R S D T L Pen H k OH) 238 (C NMeR S D T L C Dab OH) 239 (NH2 C NMeR S D T L Pen dihydro-W k OH) 240 (NH2 K W C NMeR S D T L Pen OH) 241 (P C NMeR S D T L Pen OH) 242 (NH2 k C NMeR S D T L Pen OH) 243 (NH2 C NMeR S D T L Pen W k OH) 244 (NH2 C NMeR S D T L Pen k OH) 245 (NH2 C NMeR S D T L Pen dihydro-W k OH) 246 (NH2 C NMeR S D T L Pen R k OH) 247 (NH2 C NMeR S D T L Pen W K OH) 248 (NH2 C NMeR S D T L Pen E k OH) 249 (NH2 C NMeR S D T L Pen OMeY k OH) 250 (NH2 K H C NMeR S D T L Pen OH) 251 (NH2 k C NMeR S D T L Pen OH) 252 (NH2 C R S D T L Pen k OH) 253 (NH2 Pen R S D T L C k OH) 254 (NH2 C NMeR S D T L C G E k OH) 255 (E C NMeR S D T L Pen OH) 256 (NH2 C NMeR S D T L Pen L k OH) 257 (NH2 C NMeR S D T L C G E K OH) 258 (NH2 C NMeR S D T L Pen k OH) 259 (NH2 C NMeR S D T L Pen Y k OH) 260 (R C NMeR S D T L Pen OH) 261 (NH2 C NMeR S D T L C G E K OH) 262 (NH2 C NMeR S D T L Pen k OH) 263 (NH2 C NMeR S D T L Pen k OH) 264 (NH2 k C NMeR S D T L Pen OH) 265 (NH2 C NMeR S D T L Pen S k OH) 266 (NH2 C NMeR S D T L Pen k OH) 267 (NH2 Pen R S D T L Pen k OH) 268 (NH2 C NMeR S D T L Pen N k OH) 269 (NH2 C NMeR S D T L Pen A(3,3 k OH) diphenyl) 270 (NH2 C NMeR S D T L Pen 4MeF k OH) 271 (N C NMeR S D T L Pen OH) 272 (NH2 C NMeR S D T L Pen W k OH) 273 (NH2 C NMeR S D T L Pen W k OH) 274 (NH2 C NMeR S D T L Pen W k OH)

(617) TABLE-US-00005 TABLE 5 Illustrative Peptide sequences Seq ID NO: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 275 (NH2 C NMeR S D T L Pen W OH) 276 (NH2 Pen NMeR S D T L Pen W NMeK OH) 277 (NH2 L Pen NMeR S D T L Pen W OH) 278 (NH2 Pen Cit S D T L Pen W k OH) 279 (NH2 C NMeR S D T L C W k OH) 280 (NH2 Pen NMeR S D T L Pen W F k OH) 281 (NH2 C NMeR S D T L Pen W k OH) 282 (NH2 C NMeR S D T L Pen W OH) 283 (NH2 Pen NMeR S D T L Pen W Y NMeK OH) 284 (NH2 S Pen NMeR S D T L Pen W OH) 285 (NH2 Pen NMeR S D T L Pen W H k OH) 286 (NH2 Pen NMeR S D T L Pen W k OH) 287 (NH2 Pen NMeR S D T L Pen W e k OH) 288 (NH2 Pen NMeR S D T L Pen W e k OH) 289 (NH2 C NMeR S D T Ogly Pen W k OH) 290 (NH2 Pen NMeR S D T L Pen W E k OH) 291 (NH2 pen NMeR S D T L pen W k OH) 292 (NH2 Pen NMeR S D T L Pen W N k OH) 293 (NH2 Pen NMeR S D T L Pen W NMe-k OH) 294 (NH2 C NMeR S D T L Pen W OH) 295 (NH2 C NMeR S D T L Pen W k OH) 296 (NH2 C NMeR S D T L Pen W k OH) IDA 297 (NH2 Pen NMeR S D T L Pen W k OH) 298 (NH2 C NMeR S D T L Pen W OH) 299 (NH2 Pen NMeR S D T L Pen 2- E k OH) Nal 300 (NH2 C NMeR S D T L Pen f OH) 301 (NH2 Pen NMeR S D T L Pen W L k OH) 302 (NH2 H Pen NMeR S D T L Pen W OH) 303 (NH2 Pen NMeR S D T L Pen w k OH) 304 (NH2 Pen NMeR S D T L Pen W E NMe-k OH) 305 (NH2 Pen NMeR S D T L Pen W R k OH) 306 (NH2 Pen NMeR S D T L Pen 3,3- E k OH) diPhe 307 (NH2 Pen NMeR S D T L Pen W E k OH) 308 (NH2 C NMeR S D T L Pen W E k OH) 309 (NH2 Pen NMeR S D T L Pen f e k OH) 310 (NH2 E Pen NMeR S D T L Pen W OH) 311 PEG4 (NH2 C NMeR S D T L Pen f OH) 312 (NH2 Pen NMeR S D T L Pen W 2- k OH) Nal 313 (NH2 C NMeR S D T L Pen w OH) 314 (NH2 C NMeR S D T L Pen w OH) 315 (NH2 Pen NMeR S D T L Pen W Y k OH) 316 (NH2 Pen NMeR S D T L Pen W e k OH) 317 (NH2 C peptoid S D T L Pen W k OH) 318 (NH2 C NMeR S D T L Pen W k OH) 319 (NH2 C NMeR S D T L Pen W k OH) 320 (NH2 Pen NMeR S D T Nle Pen W E k OH) 321 (NH2) C NMeR S D T L C W k OH) 322 (NH2 R Pen NMeR S D T L Pen W OH) 323 (NH2 C NMeR S D T L Pen W k OH) 324 (NH2 Pen NMeR S D T L Pen W W k OH) 325 (NH2 Pen NMeR S D T L Pen W P k OH) 326 NH2 C NMeR S D T L C W NH2 327 (NH2 Pen NMeR S D T L Pen Y k OH) 328 (NH2 Pen NMeR S D T L Pen W b-h-E k OH) 329 (NH2 Pen NMeR S D T L Pen W b-h-E k OH) 330 (NH2 F Pen NMeR S D T L Pen W OH) 331 (NH2 Pen NMeR S D T L Pen W Beta-E k OH) 332 (Glutaric C NMeR S D T L C W k OH) NH2id 333 (NH2 Pen NMeR S D T L Pen W k OH) 334 (NH2 Pen NMeR S D T L Pen F e k OH) 335 (NH2 Pen NMeR S D T L Pen W E NMeK OH) 336 (NH2 C NMeR S D T L Pen W k OH) 337 (NH2 Pen NMeR S D T L Pen f k OH) 338 (NH2 Pen NMeR S D T L Pen W B- k OH) homoPhe 339 NH2 Pen NMeR S D T L Pen f NH2 340 (NH2 Pen NMeR S D T L Pen W d k OH) 341 (NH2 Pen NMeR S D T L Pen F(4- E k OH) CF3) 342 (NH2 Pen NMeR S D T L Pen F(4- e k OH) CF3) 343 (NH2 k C NMeR S D T L C W k OH) 344 (NH2 Pen NMeR S D T L Pen W k OH) IDA 345 (NH2 Pen NMeR S D T L Pen W k OH) IDA 346 (NH2 Pen NMeR S D T L Pen W E k OH) 347 (NH2 Pen NMeR S D T L Pen W S k OH) 348 (NH2 Pen NMeR S D T L Pen f k OH) 349 (NH2 C NMeR S D T L C W k OH) 350 (NH2 C NMeR S D T L Pen W k OH) 351 (NH2 C NMeR S D T Nle C W k OH) 352 (NH2 C NMeR S D T L Pen W k OH) IDA 353 (NH2 Pen NMeR S D T L Pen f E k OH) 354 (NH2 Pen NMeR S D T L Pen W Bip k OH) 355 (NH2 Pen NMeR S D T L Pen W E k OH) 356 (NH2 Pen NMeR S D T L Pen W OH) 357 (NH2 Pen NMeR S D T L Pen W K OH) 358 (NH2 Pen NMeR S D T L Pen b-h-W E k OH) 359 (NH2 Pen NMeR S D T L Pen W 1- k OH) Nal

(618) TABLE-US-00006 TABLE 6 Illustrative Peptide Sequences SEQ ID NO: 1 2 3 4 5 6 7 8 9 10 11 12 13 360 (NH2 Pen NMeR S D T L Pen W e k OH) 361 (NH2 Pen NMeR S D(OMe) T L Pen W E k OH) 362 (NH2 Pen NMeR S D T L Pen W E k OH) 363 (NH2 Pen NMeR S D T L Pen F(4- e k OH) CF3) 364 (NH2 k C NMeR S D T L C W k OH) 365 (NH2 Pen NMeR S D T L Pen 2-Nal Bip k OH) 366 (NH2 Pen NMeR S D T L C Tic e k OH) 367 (NH2 C NMeR S D T L Pen W k OH) 368 (NH2 Pen NMeR S D T L Pen W E(OMe) k OH) 369 (NH2 Pen NMeR S D T L Pen F(4- E NMe-k OH) COOH) 370 (NH2 Pen NMeR S D T L Pen W D k OH) 371 (NH2 Pen NMeR S D T L Pen f OH) 372 (NH2 Pen NMeR S D T L Pen W f k OH) 373 (NH2 Pen NMeR S D T L Pen F(2- e k OH) carbamoyl) 374 (NH2 Pen NMeR S D T L Pen F(4- - k OH) COOH) homoGlu 375 (NH2 Pen NMeR S D T L Pen W P k OH) 376 (NH2 Pen NMeR S D T L Pen F(3,4- E k OH) diCl) 377 (NH2 Pen NMeR S D T L Pen W Q k OH) 378 (NH2 Pen NMeR S D T L Pen F(4- E k OH) COOH) 379 (NH2 Pen NMeR S D T L Pen D-1-Nal E k OH) 380 (NH2 Pen NMeR S D T L Pen F(4- - k OH) COOH) homoGlu 381 (NH2 Pen NMeR S D T L Pen W N k OH) 382 (NH2 Pen NMeR S D T L Pen F(4- E NMe-K OH) tBu) 383 (NH2 Pen NMeR S D T L Pen F(4CF3) e k OH) 384 (NH2 Pen NMeR S D T L Pen 2-Nal E NMe-k OH) 385 (NH2 Pen NMeR S D T L Pen F(2,4- E k OH) diCl) 386 (NH2 Pen NMeR S D T L Pen 2-Nal - NMe-k OH) homoGlu 387 (NH2 Pen NMeR S D T L Pen 2-Nal e NMe-k OH) 388 (NH2 Pen NMeR S D T L Pen HPhe e k OH) 389 (NH2 Pen NMeR S D T L Pen 1-Nal E k OH) 390 (NH2 Pen NMeR S D T L Pen D-2-Nal E k OH) 391 (NH2 Pen NMeR S D T L Pen W k OH) 392 (NH2 Pen NMeR S D T L Pen W Cit k OH) 393 (NH2 Pen NMeR S D T L Pen H e k OH) 394 (NH2 Pen NMeR S D T L Pen F(4- E k OH) tBu) 395 (NH2 Pen NMeR S D T L Pen W F k OH) 396 (NH2 Pen NMeR S D T L Pen W E Dab OH) 397 (NH2 Pen NMeR S D T L Pen 1-Nal f k OH) 398 (NH2 k C NMeR S D T L C W k OH) 399 (NH2 Pen NMeR S D T L Pen 1-Nal h k OH) 400 (NH2 Pen NMeR S D T L Pen 1-Nal l k OH) 401 (NH2 Pen NMeR S D T L Pen Bip - NMeK OH) homoGlu 402 (NH2 Pen NMeR S D T L Pen H Y k OH) 403 (NH2 Pen NMeR S D T L Pen f e k OH) 404 (NH2 C NMeR S D T L C W OH) 405 (NH2 Pen NMeR S D T L Pen Y E k OH) 406 (NH2 Pen NMeR S D T L Pen 2-Nal Y k OH) 407 (NH2 Pen NMeR S D T L Pen 1-Nal E k OH) 408 (NH2 C NMeR S D T L Pen W OH) 409 (NH2 Pen NMeR S D T L Pen 1-Nal - NMe-K OH) homoGlu 410 (NH2 Pen NMeR S D T L Pen H E k OH) 411 (NH2 Pen NMeR S D T L Pen 1-Nal t k OH) 412 (NH2 Pen NMeR S D T L Pen 2-Nal f k OH) 413 (NH2 Pen NMeR S D T L Pen W Beta-E k OH) 414 (NH2 Pen NMeR S D T L Pen W P K OH) 415 (NH2 Pen NMeR S D T L Pen W p K OH) 416 (NH2 Pen NMeR S D T L Pen 2-Nal - k OH) homoGlu 417 (NH2 Pen NMeR S D T L Pen 2-Nal y k OH) 418 (NH2 Pen NMeR S D T L Pen w E k OH) 419 (NH2 Pen NMeR S D T L Pen F(4- E NMe-k OH) tBu) 420 (NH2 Pen NMeR S D T L Pen F(4- E k OH) COOH) 421 (NH2 Pen NMeR S D T L Pen 2-Nal e k OH) 422 (NH2 Pen NMeR S D T L Pen 1-Nal e NMe-k OH) 423 (NH2 Pen NMeR S D T L Pen Tic e k OH) 424 (NH2 Pen NMeR S D T L Pen W E k OH) 425 (NH2 Pen NMeR S D T L Pen 1-Nal r k OH) 426 (NH2 Pen NMeR S D T L Pen 1-Nal Tic k OH) 427 (NH2 Pen NMeR S D T L Pen Bip E k OH) 428 (NH2 Pen NMeR S D T L Pen 1-Nal - k OH) homoGlu 429 (NH2 Pen NMeR S D T L Pen f E k OH) 430 (NH2 Pen NMeR S D T L Pen W NMeE k OH) 431 (NH2 Pen NMeR S D T L Pen 1-Nal e k OH) 432 (NH2 Pen NMeR S D T L Pen 2-Nal e k OH) 433 (NH2 Pen NMeR S D T L Pen F(4- - NMeK OH) tBu) homoGlu 434 (NH2 Pen NMeR S D T L Pen 2-Nal h k OH) 435 (NH2 Pen NMeR S D T L Pen 2-Nal l k OH) 436 (NH2 Pen NMeR S D T L Pen 2-Nal r k OH) 437 (NH2 C NMeR S D T L Pen W OH) 438 (NH2 Pen NMeR S D T L Pen 1-Nal E NMe-k OH) 439 (NH2 Pen NMeR S D T L Pen 1-Nal E NMeK OH) 440 (NH2 Pen NMeR S D T L Pen 1-Nal E NMe-k OH) 441 (NH2 Pen NMeR S D T L Pen 1-Nal - NMe-k OH) homoGlu 442 (NH2 Pen NMeR S D T L Pen HPhe E k OH) 443 (OH Beta- Pen NMeR S D T L Pen W E OH) Ala 444 (NH2 Pen NMeR S D T L Pen F(4- - NMe-k OH) tBu) homoGlu 445 (NH2 Pen NMeR S D T L Pen F(4- E k OH) COOH) 446 (NH2 Pen NMeR S D T L Pen W E k OH) 447 (NH2 Pen NMeR S D T L Pen W Tic k OH) 448 (NH2 Pen NMeR S D T L Pen W e k OH) 449 (NH2 Pen NMeR S D T L Pen 2-Nal Tic k OH) 450 (NH2 C NMeR S D T L Pen W k OH) 451 (NH2 Pen NMeR S D T L Pen W y k OH) 452 (NH2 Pen NMeR S D T L Pen W e k OH) 453 (NH2 Pen NMeR S D T L Pen F(4- - k OH) COOH) homoGlu 454 (NH2 Pen NMeR S D T L Pen W e k OH) 455 (NH2 Pen NMeR S D T L Pen Y e k OH) 456 (NH2 Pen NMeR S D T L Pen F(3- e k OH) carbamoyl) 457 (NH2 Pen NMeR S D T L Pen F(4- - k OH) tBu) homoGlu 458 (NH2 Pen NMeR S D T L Pen F(4- e k OH) COOH) 459 (NH2 Pen NMeR S D T L Pen F(2,4- e k OH) Cl) 460 (NH2 Pen NMeR S D T L Pen Bip - NMe-k OH) homoGlu 461 (NH2 Pen NMeR S D T L Pen F(3,4- e k OH) Cl) 462 (NH2 Pen NMeR S D T L Pen W F(4- k OH) COOH) 463 (NH2 Pen NMeR S D T L Pen F(4- e k OH) tBu) 464 (NH2 Pen NMeR S D T L Pen Bip - k OH) homoGlu 465 (NH2 Pen NMeR S D T L Pen F(4-F) e k OH) 466 (NH2 Pen NMeR S D T L Pen Bip e k OH) 467 (NH2 Pen NMeR S D T L Pen W w k OH) 468 (NH2 Pen NMeR S D T L Pen Bip E NMeK OH) 469 (NH2 Pen NMeR S D T L Pen Bip E NMe-k OH) 470 (NH2 Pen NMeR S D T L Pen F(4- e k OH) OMe) 471 (NH2 Pen NMeR S D T L Pen W NMeK OH) 472 (NH2 Pen NMeR S D T L Pen 2-Nal E k OH) 473 (NH2 Pen NMeR S D T L Pen 2-Nal E NMeK OH) 474 (NH2 Pen NMeR S D T L Pen W h k OH) 475 (NH2 Pen NMeR S D T L Pen 2-Nal E NMe-k OH) 476 (NH2 Pen NMeR S D T L Pen 2-Nal - NMeK OH) homoGlu

(619) In certain embodiments of any of the formulas described herein, Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 can only be Ac when located at the N-terminus of the peptide compound, e.g., bound to the N-terminal amino acid of the peptide compound. In particular embodiments of any of the compounds of any of the various formulas described herein, Xaa.sup.1 is Ac, and Xaa2 and Xaa.sup.3 are both absent or any amino acid.

(620) In particular embodiments of any of the formulas described herein, Xaa.sup.1 is Ac, and Xaa.sup.2 and Xaa.sup.3 are absent or any amino acid. In certain embodiments, Xaa.sup.1 and Xaa.sup.2 are absent and Xaa.sup.3 is Ac.

(621) In particular embodiments of any of the formulas described herein, any one or more of Xaa.sup.1, Xaa.sup.2, or Xaa.sup.3 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, Cys, homoCys, Pen, and D-Orn. In particular embodiments when Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 are absent, two monomer subunits of the peptide dimer compounds are linked with -amine of the N-terminal amino acid. In particular embodiments, the two subunits are linked with side chain amine, thio group or any functionality capable of linking through the linker of amino acid or the -amine group of Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3. In particular embodiments, Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is D-Lys, N-Me-Lys, or DN-Me-Lys. In particular embodiments, Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is D-Lys, N-Me-Lys, or D-N-Me-Lys, and is located at the N-terminus of the peptide. In particular embodiments, both subunits of a peptide dimer compound comprise an Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 selected from one of these residues, and the two subunits are linked via their respective N-termini.

(622) In particular embodiments of any of the formulas described herein, any one or more of Xaa.sup.1, Xaa.sup.2, or Xaa.sup.3 is selected from the group consisting of: any amino acid with an amine side chain, Lys, D-Lys, N-Me-Lys, D-N-Me-Lys, Orn, Dab, Dap, homoLys, D-Dap, D-Dab, DOrn, Cys, homoCys, Pen, D-homoCys, D-Cys, D-Pen, Asp, Glu, D-Asp, D-Glu and homoSer, Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, this residue is located at the N-terminus of the peptide. In certain embodiments, Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 is selected from the group consisting of: Asp, Glu, homoGlu, D-Asp, D-Glu, D-homoGlu, N-Me-Glu, N-Me-Asp, N-Me-D-Glu, and N-Me-D-Asp. In particular embodiments, this residue is located at the N-terminus of the peptide. In particular embodiments, the two N-terminal amino acids of each subunit of a peptide dimer compound possess acid functionality, and they are linked through retroinverse linking by a diamine linker. In particular embodiments, both subunits of a peptide dimer compound comprise an Xaa.sup.1, Xaa.sup.2 or Xaa.sup.3 selected from one of these residues, and the two subunits are linked via their respective N-termini.

(623) In addition, the present invention includes compounds, including cyclic peptide dimers, monomer peptide subunits of cyclic peptide dimers, C-N cyclic monomer peptides, and C-N cyclic dimer peptides, and C-N cyclic monomer peptide subunits of C-N cyclic dimers, comprising, consisting essentially of, or consisting of one or more (e.g., two) of any of the amino acid sequences described herein, e.g., in any of the formula, or shown in any of the accompanying tables or figures, e.g., without requiring the presence of any N-terminal modification such as Ac or any C-terminal modification such as NH.sub.2, or without requiring the presence of a linker.

(624) The present invention further includes any of the compounds described herein having an alternative N-terminal or C-terminal group. For example, those compounds that show an N-terminal Ac group are also encompassed when their N-terminus is either the unaltered N-terminus of an amino acid, or when a different group is present, and those compounds that show a C-terminal NH.sub.2 group are also encompassed when their C-terminus is either the unaltered C-terminus of an amino acid, or when a different group is present.

(625) The invention further includes a method of manufacturing a peptide compound of the present invention, comprising synthesizing a peptide having a sequence as described herein, and introducing an intramolecular bond between two residues of the peptide (or allowing the intramolecular bond to form). In particular embodiments, the method further includes modifying one or both of the C-terminus and N-terminus of the peptide. In further embodiments, the method includes conjugating one or more linker(s) to the peptide. In related embodiments, the invention includes a method of preparing a peptide dimer compound comprising: (i) synthesizing a peptide having a sequence as described herein, and introducing an intramolecular bond between two residues of the peptide (or allowing the intramolecular bond to form), and conjugating one or more linker(s) to the peptide; (ii) synthesizing a peptide having a sequence as described herein (e.g., the same sequence as for step (i)), and introducing an intramolecular bond between two residues of the peptide (or allowing the intramolecular bond to form); and (iii) conjugating the peptide of step (i) to the peptide of step (ii) via the linker attached to the peptide of step (i).

(626) In particular embodiments, the present invention includes a polynucleotide encoding any of the peptide sequences disclosed herein. In particular embodiments, the polynucleotide is DNA, RNA, cDNA, or mRNA, including single-stranded, double-stranded polynucleotide forms thereof, and modified forms thereof. In certain embodiments, the incention includes a vector, e.g., an expression vector or gene therapy vector, comprising a polynucleotide encoding any of the peptides described herein. The vector may further include a promoter and/or other regulatory sequences operably linked to the sequence encoding the peptide sequence described herein. The present invention further includes cells comprising an exogenous or introduced peptide or polynucleotide described herein.

(627) In particular embodiments of any of the various Formulas described herein, peptides having the same structure or sequence as disclosed in any one or more of PCT/US2013/064439, PCT/US2014/032391 or PCT/US2014/032392 are excluded. In some embodiments of the present invention, the C-N cyclic peptides comprise a sequence or structure set forth in any of PCT/US2013/064439, PCT/US2014/032391, PCT/US2014/032392 or PCT/US2014/031243, or U.S. provisional applications U.S. 62/192,934, 62/058,506, or 62/058,510, or a U.S. utility application titled Novel a4b7 Peptide Monomer and Dimer Antagonist filed on Sep. 30, 2015. In certain embodiments of the present invention, the cyclic dimer peptides or subunits thereof comprise a sequence or structure set forth in any of PCT/US2013/064439, PCT/US2014/032391, PCT/US2014/032392 or PCT/US2014/031243, or U.S. provisional applications U.S. 62/192,934, 62/058,506, or 62/058,510, or U.S. utility application Ser. No. 14/872,975, each of which is incorporated by reference in its entirety.

(628) Cyclic Peptide Structure and Biological Activity

(629) The present invention provides various novel C-N cyclic integrin antagonist peptides and various novel antagonist disulfide peptide cyclic dimer molecules. These compounds have been tested to more clearly characterize the increased affinity for 47 binding, increased selectivity against 41, and/or increased stability in simulated intestinal fluid (SIF). These novel, C-N cyclic antagonist molecules and various novel antagonist disulfide peptide cyclic dimer molecules demonstrate high binding affinity with 47, thereby preventing binding between 47 and the MAdCAM ligand. Accordingly, these C-N cyclic monomer and dimer peptide molecules and and disulfide peptide cyclic dimer molecules have shown to be effective in eliminating and/or reducing the inflammation process in various experiments.

(630) The present invention thus provides various C-N cyclic monomer and C-N cyclic dimer peptide compounds and various antagonist disulfide peptide cyclic dimer molecules which bind or associate with the 47 integrin to disrupt or block binding between 47 and the MAdCAM ligand. The various C-N cyclic peptide compounds and various disulfide peptide cyclic dimer molecules of the invention may be constructed solely of natural amino acids. Alternatively, the C-N cyclic peptide compounds and disulfide peptide cyclic dimers may include non-natural amino acids including, but not limited to, modified amino acids. Modified amino acids include natural amino acids which have been chemically modified to include a group, groups, or chemical moiety not naturally present on the amino acid. The C-N cyclic peptide compounds and disulfide peptide cyclic dimer compounds of the invention may additionally include D-amino acids. Still further, the C-N cyclic peptide compounds and disulfide peptide cyclic dimer compounds of the invention may include amino acid analogs.

(631) The present invention also includes peptides comprising the same structure as shown in Formulas (I), (II), (III), (VI), (V), (VI), (VII), or (VIII), or any of the other formulas or tables described herein comprising an intramolecular bond, e.g. a disulfide bond, a lactam bond, an olefin bond, a 1,2,3-triazole ring, or a thioether bond, but where the intramolecular bond is in the reverse orientation, i.e., the two amino acid residues participating in the intramolecular bond are switched with each other. In certain embodiments, one or both monomer subunits of the cyclic dimer peptide comprises an intramolecular bond, e.g., between Xaa.sup.4 and Xaa.sup.10 of Formula (I) or corresponding positions in other peptides. In such embodiments of the invention, it may generally be considered that the amino acid residues or other chemical moieties shown at Xaa.sup.4 of Formula (I), or corresponding positions in other peptides, are instead present at Xaa.sup.10 of Formula (I) or corresponding positions in other peptides, or where the amino acid residues shown at Xaa.sup.10 are instead present at Xaa.sup.4.

(632) The present invention also includes peptides comprising a thioether bond comprising the same structure as shown in Formulas (I), (II), (III), (VI), (V), (VI), (VII), or (VIII), or any of the other formulas or tables described herein, but where the thioether bond is in the reverse orientation. In such embodiments of the invention, it may generally be considered that the amino acid residues or other chemical moieties shown at Xaa.sup.4 of Formula (VI) or the corresponding position are instead present at Xaa.sup.10 of Formula (VI) or the corresponding position, and the amino acid residues shown at Xaa.sup.10 of Formula (VI) or the corresponding position are instead present at Xaa.sup.4 of Formula (VI) or the corresponding position. For example, a peptide comprising a thioether bond having the same structure as shown in Formula (VI), the amino acid residue comprising the sulfur of the resulting thioether bond is located at Xaa.sup.4 instead of Xaa.sup.10, and the amino acid residue or other moiety having a carbon side chain capable of forming a thioether bond with Xaa.sup.4 is located at Xaa.sup.10. In this reverse orientation, however, the amino acid or chemical moiety at position Xaa.sup.10 is one that comprises a free amine. For example, in particular embodiments, the amino acid at Xaa.sup.10 or the corresponding position is a protected homoserine, such as, e.g., homoserine (OTBDMS). Thus, in particular reverse orientation embodiments of Formula (VI), Xaa.sup.10 is an amino acid residue having a side chain with one or two carbons, and forming a thioether bond with Xaa.sup.4, and Xaa.sup.4 is selected from the group consisting of Cys, N-Me-Cys, D-Cys, HCys, Pen, and D-Pen. Specific examples of amino acid residues and other chemical moieties present at corresponding positions of other formulas and tables are described herein.

(633) In particular embodiments of any of the peptides herein comprising an intramolecular bond, e.g. a disulfide bond, a lactam bond, an olefin bond, a 1,2,3-triazole ring, or a thioether bond, including those comprising a structure of any one of Formulas (I), (II), (III), (VI), (V), (VI), (VII), or (VIII), or any of the other formulas or tables described herein, the intramolecular bond is in the reverse order, such that the amino acid residues and chemical moieties corresponding to Xaa.sup.4 of Formula (VI) are instead present in the position corresponding to Xaa.sup.10, and the amino acid resides corresponding to Xaa.sup.10 of Formula (VI) are instead present in the position corresponding to Xaa.sup.4. In this reverse orientation, the amino acid or chemical moiety corresponding to position Xaa.sup.10 is one that comprises a free amine.

(634) In some embodiments, the present invention also includes peptides comprising a reverse order thioether bond embodiments of (I), (II), (III), (VI), (V), (VI), (VII), or (VIII), or any of the other formulas or tables described herein, wherein Xaa.sup.10 of formula (VI) or a corresponding amino acid, is an amino acid, aliphatic acid, alicyclic acid, or modified 2-methyl aromatic acid having a side chain with one or two carbons, and capable of forming a thioether bond with Xaa.sup.4; and Xaa.sup.4 or a corresponding amino acid, is selected from the group consisting of Cys, N-MeCys, D-Cys, HCys, Pen, D-Pen, and Pen(O). In this reverse orientation, the amino acid or chemical moiety at position Xaa.sup.10 is one that comprises a free amine. One example of an amino acid or chemical moiety that provides a free amine is homoserine or a protected homoserine, e.g., homserine(OTBDMS).

(635) Some antagonist disulfide cyclic dimers have been shown to be gastrointestinal stable and provide high levels of specificity and affinity for the 47 integrin. Some implementations of the present invention provide a disulfide cyclic dimer comprising a half-life of greater than 60 minutes or greater than 180 minutes when exposed to simulated intestinal fluids (SIF). Some implementations further provide a DRP comprising a half-life from approximately 1 minute to approximately 60 minutes.

(636) In certain embodiments, cyclic peptides and/or C-N cyclic peptides of the present invention inhibit or reduce binding between between 47 and the MAdCAM ligand. In certain embodiments, a cyclic peptide or a C-N cyclic peptide of the present invention reduces binding of 47 and the MAdCAM ligand by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% as compared to a negative control peptide. Methods of determining binding are known in the art and include ELISA assays, for example.

(637) In particular embodiments, a cyclic peptide of the present invention has an IC50 of <500 nM, <250 nM, <100 nM, <50 nM, <25 nM, <10 nM, <5 nM, <3 nM, or <2 nM, e.g., in binding to 47 or inhibiting 47 from binding its receptor. In certain embodiments, a C-N cyclic peptide of the present invention has an IC50 of <500 nM, <250 nM, <100 nM, <50 nM, <25 nM, or <10 nM. Methods of determining activity are known in the art and include any of those described in the accompanying Examples.

(638) Some C-N cyclic peptides and/or cyclic peptides of the invention are gastrointestinal stable and provide high levels of specificity and affinity for the OP integrin. Some implementations of the present invention provide cyclic dimer peptides and C-N cyclic monomer and dimer peptide molecules comprising a half-life of greater than 60 minutes or greater than 180 minutes when exposed to simulated intestinal fluids (SIF). Some implementations further provide cyclic and/or C-N cyclic peptides comprising a half-life from approximately 1 minute to approximately 180 minutes. In some instances, these C-N cyclic peptides are stable to gastric environment under reduced conditions with half-life >120 min when tested in DTT (Dithiothreitol) assay.

(639) In certain embodiments, cyclic dimer peptide and/or C-N cyclic peptides of the present invention have increased stability, increased gastrointestinal stability, or increased stability in stimulated intestinal fluid (SIF), as compared to a control peptide. In particular embodiments, a control peptide is a peptide having the identical or a highly related amino acid sequence (e.g., >90% sequence identity) as the cyclic dimer peptide or C-N cyclic peptide, but which does not form a cyclic or C-N cyclic structure and/or include an intramolecular bridging bond. In particular embodiments, the only difference between the cyclic dimer peptide or the C-N cyclic peptide and the control peptide is that the cyclic dimer peptide or C-N cyclic peptide comprises one or more amino acid substitutions that introduce one or more amino acid residues into the cyclic dimers or C-N cyclic peptides, wherein the introduced residue(s) forms an intramolecular bond with another residue in the C-N cyclic peptide.

(640) Methods of determining the stablity of a peptide are known in the art. In certain embodiments, the stability of cyclic dimer peptides and/or C-N cyclic peptides is determined using an SIF assay, e.g., as described in the accompanying Examples. In particular embodiments, a cyclic dimer peptide or C-N cyclic peptide has a half-life under a given set of conditions (e.g., temperature) of greater than 1 minute, greater than 10 minutes, greater than 20 minutes, greater than 30 minutes, greater than 60 minutes, greater than 90 minutes, greater than 120 minutes, greater than 3 hours, or greater than four hours when exposed to SIF. In certain embodiments, the temperature is about 25 C., about 4 C., or about 37 C., and the pH is a physiological pH, or a pH about 7.4.

(641) In some embodiments, the half-life is measured in vitro using any suitable method known in the art, e.g., in some embodiments, the stability of cyclic dimer peptide and/or C-N cyclic peptides of the present invention is determined by incubating the peptide dimer with pre-warmed human serum (Sigma) at 37 C. Samples are taken at various time points, typically up to 24 hours, and the stability of the sample is analyzed by separating the cyclic dimer peptide and/or C-N cyclic peptide from the serum proteins and then analyzing for the presence of the cyclic dimer peptide and/or C-N cyclic peptides of interest using LC-MS.

(642) In some embodiments, a cyclic dimer peptide or C-N cyclic peptide of the present invention exhibits improved solubility or improved aggregation characteristics as compared to a control peptide. Solubility may be determined via any suitable method known in the art. In some embodiments, suitable methods known in the art for determining solubility include incubating C-N cyclic peptides in various buffers (Acetate pH4.0, Acetate pH5.0, Phos/Citrate pH5.0, Phos Citrate pH6.0, Phos pH 6.0, Phos pH 7.0, Phos pH7.5, Strong PBS pH 7.5, Tris pH7.5, Tris pH 8.0, Glycine pH 9.0, Water, Acetic acid (pH 5.0 and other known in the art) and testing for aggregation or solubility using standard techniques. These include, but are not limited to, visual precipitation, dynamic light scattering, Circular Dichroism and fluorescent dyes to measure surface hydrophobicity, and detect aggregation or fibrillation, for example. In some embodiments, improved solubility means the C-N cyclic peptides is more soluble in a given liquid than is a control peptide.

(643) In some embodiments, the C-N cyclic peptides of the present invention have less degradation (i.e., more degradation stability), e.g., greater than or about 10% less, greater than or about 20% less, greater than or about 30% less, greater than or about 40 less, or greater than or about 50% less degradation than a control peptide. In some embodiments, degradation stability is determined via any suitable method known in the art. In some embodiments, suitable methods known in the art for determining degradation stability include the method described in Hawe et al J Pharm Sci, VOL. 101, NO. 3, 2012, p 895-913, incorporated herein in its entirety. Such methods are in some embodiments used to select potent C-N cyclic peptides with enhanced shelf lifes.

(644) In certain embodiments, C-N cyclic peptides of the present invention inhibit or reduce 47-mediated inflammation. In related embodiments, C-N cyclic peptides of the present invention inhibit or reduce 47-mediated secretion of one or more cytokines Methods of determining inhibition of cytokine secretion and inhibition of signaling molecules are known in the art.

(645) In certain embodiments, C-N cyclic peptides of the present invention demonstrate increased binding selectivity. In certain instances, C-N cyclic peptides of the present invention binds to 47 with at least a two-fold, three-fold, five-fold, or ten-fold greater affinity than the C-N cyclic peptides bind to 41.

(646) The C-N cyclic peptides of the present invention demonstrate increased potency as a result of substituting various natural amino acyl residues with N-methylated analog residues. For example, the C-N cyclic peptides shown in Table 7 represent subunit monomer sequences that are substituted with N(alpha)methylated arginine.

(647) In certain embodiments, compounds of the present invention are homo or hetero cyclic dimers formed by linking two monomer subunits at their C- and N-terminuses using two linker moieties. Cyclic dimerization of the monomer subunits represented by SEQ ID NOs: 1-146 demonstrate increased potency over their non-dimerized, monomer analogs. Some cyclic dimer compounds of the present invention demonstrated further increased potency as a result of substituting various natural amino acyl residues with N-methylated analog residues. For example, SEQ ID NOs.: 1-38, 46-52, 54-135, and 137-146 represent subunit monomers sequences that were substituted with N(alpha)methylated arginine. Further still, some dimer compounds of the present invention comprise monomer subunits that undergo independent cyclization, whereby the cyclized structures demonstrate increased stability over their non-cyclized monomer and cyclic dimer analogs.

(648) Cyclic dimerization of the monomer peptide subunits of the present invention generally demonstrate increase stability, as compared to the monomer disulfide subunit peptides. Further, substitutions at arginine with N-Me-Arg increased half-life substantially in SIF. In some embodiments, substitution of Cys with Penicillamine (Pen) increased stability significantly in simulated intestinal fluids (SIF). The substitution of Cys with Pen also increased stability under reduced conditions (DTT) indicating improved gastric stability.

(649) Selectivity potency assays were performed for some of the monomer peptides, and their respective cyclic homodimer molecules Through cyclic dimerization, significant improvement in potency was achieved for 47 in ELISA as well as cell adhesion assays. In addition, cyclic dimerizations lead to significant improvement achieved in selectivity against 41 through improved potency for 47. The cyclically dimerized peptides also demonstrate low efficacy for 41 when compared to 47, thereby indicating selectivity against 47.

(650) According to the protocols discussed herein, applicant successfully synthesized, purified and dimerized various integrin antagonist cyclic dimer molecules to form cyclic homodimers. Each of these cyclic dimer molecules was subjected to an 47-MAdCAM Competition ELISA assay, an 41-VCAM Competition ELISA assay, an 47-MadCAM cell adhesion assay. For many sequences, these assays were also performed on both the monomer subunit and cyclic dimer molecules. A small sampling of these results is provided in FIG. 3.

(651) Cyclic dimerization of the monomer disulfide peptide subunits generally demonstrate increased affinity for a4b7 and/or decreased affinity for a4b1 leading to increased selectivity against a4b1, as compared to the monomer disulfide subunit peptides.

(652) Upon cyclic dimerization through C- and N-terminal linker moieties dimerization, a significant improvement in potency for 47 is observed. In addition, cyclic dimerization also leads to either a decrease of potency for 41, or no significant change in potency which leads to increased selectivity for 47 in ELISA and cell adhesion assays. When Arg is replaced with N-Me-Arg, a significant improvement in potency for 47 is acheived in both ELISA and cell adhesion assays. N(alpha)methylation further demonstrates increased molecular stability. One having skill in the art will appreciate that methylated isosteres of arginine may further demonstrate similar increases in potency and/or stability.

(653) Some compounds of the present invention are C-N cyclic homo or heterodimers formed by linking two C-N cyclic monomers via Lys residues of the respective C-N cyclic monomer subunits. Dimerization of the C-N cyclic monomer subunits shown in Table 7 demonstrated increased potency over their non-dimerized, monomer analogs. Some C-N cyclic dimer compounds of the present invention demonstrated further increased potency as a result of substituting various natural amino acyl residues with N-methylated analog residues. Some C-N cyclic dimer molecules further undergo disulfide, amide or hydrogen bonding between complimentary amino acid residues of opposing C-N cyclic monomer peptide subunits, whereby these bonds may demonstrate increased stability over other C-N cyclic monomer and dimer peptide molecules. Data illustrating the increased potency for the C-N cyclic peptide molecules of the instant invention are provided in Table 7.

(654) Referring now to Table 7, a table is provided which includes various data illustrating increased potency for various non-limiting C-N cyclic molecules in accordance with the instant invention. Potency assays were performed for various C-N cyclic dimer molecules of the present invention. These assays were also performed for various C-N cyclic monomer subunits molecules.

(655) TABLE-US-00007 TABLE 7 Potency of representative CN cyclic peptides Cell Adhesion SEQ ID ELISA A4B7 NO: 3 4 5 6 7 8 9 10 11 a4b7 (nM) (nM) CN cyclic peptides 477 Cyclo (a NMeR S D T L a) *** >10,000 *** 478 cyclo <NH2 a NMeR S D T L n OH> >1000 479 cyclo <NH2 a NMeR S D T L n OH> *** >10,000 480 cyclo <NH2 h NMeR S D T L a OH> >1000 481 cyclo <NH2 h NMeR S D T L a OH> *** 482 cyclo <NH2 a NMeR S D T L e OH> >1000 483 cyclo <NH2 a NMeR S D T L e OH> >1000 484 cyclo <NH2 a NMeR S D T L e OH> *** >1,000 485 cyclo <NH2 k NMeR S D T L a OH> >1000 486 cyclo <NH2 k NMeR S D T L a OH> >1000 487 cyclo <NH2 k NMeR S D T L a OH> *** 488 cyclo <NH2 a NMeR S D T L l OH> *** 489 cyclo <NH2 a NMeR S D T L l OH> >1000 490 cyclo <NH2 a NMeR S D T L h OH> >1000 491 cyclo <NH2 a NMeR S D T L h OH> *** 492 cyclo <NH2 a NMeR S D T L f OH> >1000 493 cyclo <NH2 a NMeR S D T L f OH> *** 494 cyclo <NH2 f NMeR S D T L a OH> >1000 495 cyclo <NH2 f NMeR S D T L a OH> *** >10,000 496 cyclo <NH2 l NMeR S D T L a OH> >1000 497 cyclo <NH2 l NMeR S D T L a OH> *** 498 cyclo <NH2 p NMeR S D T L a OH> >1000 499 cyclo <NH2 p NMeR S D T L a OH> *** 500 cyclo <NH2 r NMeR S D T L a OH> >1000 501 cyclo <NH2 r NMeR S D T L a OH> *** 502 cyclo <NH2 A NMeR S D T L a OH> >1000 503 cyclo <NH2 A NMeR S D T L k OH> >1000 504 cyclo < a NMeR S D T L A a > >1000

(656) Table 7 demonstrates potency data for illustrative C-N cyclic integrin antagonist monomer molecules, in accordance with various representative embodiment of the present invention.

(657) According to the protocols discussed herein, applicant successfully synthesized, purified, cyclized and dimerized all of the integrin antagonist C-N cyclic molecules shown in Table 7. Each of these molecules were subjected to an 47-MAdCAM Competition ELISA assay.

(658) Cyclization of the monomer peptide sequences generally demonstrated increased potency for the peptides molecules, which lead to selectivity for 47 in ELISA and cell adhesion assay. Cyclization and dimerization of the peptide molecules are expected to lead to even greater potency and/or greater selectively for 47 in both ELISA and cell adhesion assays.

(659) Methods of Treatment and Pharmaceutical Compositions

(660) As discussed above, integrins are heterodimers that function as cell adhesion molecules. The 4 integrins, 41 and 47, play essential roles in lymphocyte migration throughout the gastrointestinal tract. They are expressed on most leukocytes, including B and T lymphocytes, where they mediate cell adhesion via binding to their respective primary ligands, namely vascular cell adhesion molecule (VCAM) and mucosal addressin cell adhesion molecule (MAdCAM). VCAM and MAdCAM differ in binding specificity, in that VCAM binds both 41 and 47, while MAdCAM is highly specific for 47.

(661) Differences in the expression profiles of VCAM and MAdCAM provide the most convincing evidence of their role in inflammatory diseases. Both are constitutively expressed in the gut; however, VCAM expression extends into peripheral organs, while MAdCAM expression is confined to organs of the gastrointestinal tract. In addition, elevated MAdCAM expression in the gut has now been correlated with several gut-associated inflammatory diseases, including Crohn's disease, ulcerative colitis, and hepatitis C.

(662) The compounds of the invention, including but not limited to those specified in the examples, possess integrin-antagonist activity.

(663) The cyclic dimer compounds of the invention, including but not limited to those specified in the examples, possess integrin-antagonist activity. In one embodiment, the condition or medical indication comprises at least one of Inflammatory Bowel Disease (IBD) (including adult IBD, pediatric IBD and adolescent IBD), ulcerative colitis, Crohn's disease, Celiac disease (e.g., nontropical Sprue), enteropathy associated with seronegative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, radiotherapy, chemotherapy, pouchitis resulting after proctocolectomy and ileoanal anastomosis, gastrointestinal cancer, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, primary sclerosing cholangitis, human immunodeficiency virus (HIV) infection in the GI tract, eosinophilic asthma, eosinophilic esophagitis, gastritis, colitis, microscopic colitis, graft versus host disease (GVDH) (including intestinal GVDH), colitis associated with radio- or chemo-therapy, colitis associated with disorders of innate immunity as in leukocyte adhesion deficiency-1, chronic granulomatous disease, glycogen storage disease type Ib, Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Wiskott-Aldrich Syndrome, or pouchitis resulting after proctocolectomy and ileoanal anastomosis and various forms of gastrointestinal cancer, osteoporosis, arthritis, multiple sclerosis, chronic pain, weight gain, and depression. In another embodiment, the condition is pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma or graft versus host disease. In addition, these cyclic dimer compounds may be useful in the prevention or reversal of these diseases when used in combination with currently available therapies, medical procedures, and therapeutic agents.

(664) The cyclic dimer compounds of the invention may be used in combination with other compositions and procedures for the treatment of disease. Additionally, the compounds of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.

(665) In one embodiment, the condition or medical indication treated or prevented using a C-N cyclic peptide of the present invention comprises at least one of Inflammatory Bowel Disease (IBD), ulcerative colitis, hepatitis C., Crohn's disease, Celiac disease (nontropical Sprue), enteropathy associated with seronegative arthropathies, mircroscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and ileoanal anastomosis, various forms of cancer, osteoporosis, arthritis, multiple sclerosis, chronic pain, weight gain, and depression. In another embodiment, the condition is pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma or graft versus host disease. In addition, these compounds may be useful in the prevention or reversal of these diseases when used in combination with currently available therapies, medical procedures, and therapeutic agents. Further uses include the treatment and prophylaxis of autoimmune diseases such as rheumatoid, immune and degenerative arthritis, intestinal adhesions, atherosclerosis, scleroderma, and hypertrophic scars, i.e. keloids.

(666) Some compounds of the present invention demonstrate high selectivity for a specific, single integrin monomer, such as 47. Other compounds of the invention demonstrate high selectively for two or more integrin heteromonomers, such as 41 and 47. Thus, some compounds of the invention may be provided for the treatment of an indication due to a specific, single integrin monomer, such as IBD or ulcerative colitis, while other compounds may be provided for the treatment of an indication due to two or more integrin heteromonomers, such as multiple sclerosis.

(667) The compounds of the invention may be used in combination with other compositions and procedures for the treatment of disease. For example, a tumor may be treated conventionally with surgery, radiation or chemotherapy combined with a C-N cyclic peptide molecule of the present invention and then a C-N cyclic peptide molecule of the present invention may be subsequently administered to the patient to extend the dormancy of micrometastases and the stabilize and inhibit the growth of any residual primary tumor. Additionally, the C-N cyclic compounds of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.

(668) In some embodiments, the present invention provides a method for treating an individual afflicted with a condition or indication characterized by integrin binding, wherein the method comprises administering to the individual an integrin antagonist cyclic dimer molecule according to formulas (I) or (II), or a C-N cyclic monomer or dimer integrin antagonist molecule according to formulas (III) or (IV). In one embodiment, a method is provided for treating an individual afflicted with a condition or indication characterized by inappropriate trafficking of cells expressing 47 to tissues comprising cells expressing MAdCAM, comprising administering to the individual an 47-antagonist cyclic dimer molecule according to formulas (I) or (II), or a C-N cyclic monomer or dimer 47-antagonist molecule according to formulas (III) or (IV), in an amount sufficient to inhibit (partially or fully) the trafficking of cells expressing 47 to tissues comprising cells expressing MAdCAM.

(669) In some embodiments, the present invention provides a method whereby a pharmaceutical composition comprising an integrin antagonist cyclic dimer molecule according to formulas (I) or (II), or any other integrin antagonist cyclic dimer molecule of the present invention; or a C-N cyclic monomer or dimer integrin antagonist molecule according to formulas (III) or (IV), or any other C-N cyclic integrin antagonist monomer or dimer molecule of the present invention, is administered to a patient as a first treatment. In another embodiment, the method further comprises administering to the subject a second treatment. In another embodiment, the second treatment is administered to the subject before and/or simultaneously with and/or after the pharmaceutical composition is administered to the subject. In other embodiment, the second treatment comprises an anti-inflammatory agent. In another embodiment, the second pharmaceutical composition comprises an agent selected from the group consisting of non-steroidal anti-inflammatory drugs, steroids, and immunomodulating agents. In another embodiment, the method comprises administering to the subject a third treatment.

(670) In one embodiment, a method is provided for treating an individual afflicted with a condition or indication characterized by 47 integrin binding, wherein the method comprises administering to the individual an effective amount of a C-N cyclic 47 integrin antagonist monomer or dimer molecule according to formula (I), or any other C-N cyclic peptide of the present invention. In some instances, a C-N cyclic 47 integrin antagonist monomer or dimer molecule according to formula (I), or any other C-N cyclic peptide of the present invention, having high specificity for 47 is administered to an individual as part of a therapeutic treatment for a condition or indication characterized by 47 integrin binding. In another embodiment, a method is provided for treating an individual afflicted with a condition or indication characterized by 47 and 41 integrin binding, wherein the method comprises administering to the individual an effective amount of a C-N cyclice 47/41 integrin antagonist monomer or dimer molecule according to formula (I), or any other C-N cyclic peptide of the present invention,

(671) In one embodiment, a method is provided for treating an individual afflicted with a condition or indication characterized by 47 integrin binding, wherein the method comprises administering to the individual an effective amount of an 47 integrin antagonist cyclic dimer molecule containing subunits selected from SEQ ID NOs: 1-146. In some instances, an 47 integrin antagonist cyclic dimer molecule having subunits selected from and corresponding to SEQ ID NOs: 1-146, and having high specificity for 47 is administered to an individual as part of a therapeutic treatment for a condition or indication characterized by 47 integrin binding.

(672) Some embodiments of the present invention further provide a method for treating an individual with 47 integrin antagonist monomer or dimer molecule, or a C-N cyclic 47 integrin antagonist monomer or dimer molecule, that is suspended in a sustained-release matrix. A sustained-release matrix, as used herein, is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. A preferred biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).

(673) Any of the methods described herein may also be practiced applying any of the sequences of formulas (V), (VI), or any peptides described herein, or in the accompanying figures or sequence listing.

(674) In some aspects, the invention provides a pharmaceutical composition for oral delivery. The various embodiments and cyclic dimer compositions of the instant invention may be prepared for oral administration according to any of the methods, techniques, and/or delivery vehicles described herein. Further, one having skill in the art will appreciate that the cyclic dimer compositions of the instant invention may be modified or integrated into a system or delivery vehicle that is not disclosed herein, yet is well known in the art and compatible for use in oral delivery of small cyclic dimer peptide molecules.

(675) Oral dosage forms or unit doses compatible for use with the cyclic dimer peptides of the present invention may include a mixture of cyclic dimer peptide active drug components, and nondrug components or excipients, as well as other non-reusable materials that may be considered either as an ingredient or packaging. Oral compositions may include at least one of a liquid, a solid, and a semi-solid dosage forms. In some embodiments, an oral dosage form is provided comprising an effective amount of a cyclic dimer peptide having subunits selected from and corresponding to SEQ ID NOs: 1-146, or a C-N cyclic monomer or dimer made of C-N monomer subunits selected from and corresponding to SEQ ID NOs:1-146, wherein the dosage form comprises at least one of a pill, a tablet, a capsule, a gel, a paste, a drink, a syrup, ointment, and suppository. In some instances, an oral dosage form is provided that is designed and configured to achieve delayed release of the peptide dimer in the subjects small intestine and/or colon.

(676) In one embodiment, an oral pharmaceutical cyclic dimer composition according to Formula (I) or (II) comprises an enteric coating that is designed to delay release of the cyclic peptide dimer in the small intestine. In at least some embodiments, a pharmaceutical composition is provided which comprises a cyclic peptide dimer compound having subunits selected from and corresponding to SEQ ID NOs: 1-146, and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. In another embodiment, an oral pharmaceutical C-N cyclic monomer or dimer composition according to Formula (III) or (IV) comprises an enteric coating that is designed to delay release of the cyclic peptide dimer in the small intestine. In at least some embodiments, a pharmaceutical composition is provided which comprises a C-N cyclic monomer or dimer molecule having C-N subunits selected from and corresponding to SEQ ID NOs: 1-146, and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. In some instances it is preferred that a pharmaceutical composition of the instant invention comprise an enteric coat that is soluble in gastric juice at a pH of about 5.0 or higher. In at least one embodiment, a pharmaceutical composition is provided comprising an enteric coating comprising a polymer having dissociable carboxylic groups, such as derivatives of cellulose, including hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate and similar derivatives of cellulose and other carbohydrate polymers.

(677) In one embodiment, a cyclic dimer or C-N cyclic monomer or dimer pharmaceutical composition is provided in an enteric coating, the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner within the subjects lower gastrointestinal system, and to avoid systemic side effects. In addition to enteric coatings, the cyclic dimer peptides of the instant invention may be encapsulated, coated, engaged or otherwise associated within any compatible oral drug delivery system or component. For example, in some embodiments a cyclic dimer peptide of the present invention is provided in a lipid carrier system comprising at least one of polymeric hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.

(678) To overcome peptide degradation in the small intestine, some implementations of the present invention comprise a hydrogel polymer carrier system in which a cyclic peptide dimer in accordance with the present invention is contained, whereby the hydrogel polymer protect the cyclic peptide dimer from proteolysis in the small intestine and/or colon. The cyclic peptide dimers of the present invention may further be formulated for compatible use with a carrier system that is designed to increase the dissolution kinetics and enhance intestinal absorption of the dimer peptides. These methods include the use of liposomes, micelles and nanoparticles to increase GI tract permeation of peptides.

(679) Various bioresponsive systems may also be combined with one or more cyclic peptide dimers, or with C-N cyclic monomers or dimers, of the present invention to provide a pharmaceutical agent for oral delivery. In some embodiments, a cyclic peptide dimer or C-N cyclic peptide monomer or dimer of the instant invention is used in combination with a bioresponsive system, such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit, chitosan and alginate) to provide a therapeutic agent for oral administration. Other embodiments include a method for optimizing or prolonging drug residence time for a cyclic peptide dimer disclosed herein, wherein the surface of the cyclic peptide dimer or C-N cyclic peptide monomer or dimer surface is modified to comprise mucoadhesive properties through hydrogen bonds, polymers with linked mucins or/and hydrophobic interactions. These modified cyclic dimer or C-N cyclic monomer or dimer molecules may demonstrate increase drug residence time within the subject, in accordance with a desired feature of the invention. Moreover, targeted mucoadhesive systems may specifically bind to receptors at the enterocytes and M-cell surfaces, thereby further increasing the uptake of particles containing the cyclic dimer or C-N cyclic monomer or dimer peptide.

(680) Other embodiments comprise a method for oral delivery of a cyclic dimer peptide or C-N cyclic monomer or dimer peptide of the present invention, wherein the cyclic dimer peptide or C-N cyclic monomer or dimer peptide is used in combination with permeation enhancers that promote the transport of the cyclic dimer peptides across the intestinal mucosa by increasing paracellular or transcellular permeation. For example, in one embodiment a permeation enhancer is combined with a cyclic dimer peptide or C-N cyclic monmer or dimer peptide of the present invention, wherein the permeation enhancer comprises at least one of a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In one embodiment, a permeation enhancer comprising sodium N[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalent association with the cyclic dimer peptide of the instant invention, wherein the permeation enhancer favors membrane transport and further dissociation once reaching the blood circulation. In another embodiment, a cyclic peptide dimer of the present invention is conjugated to oligoarginine, thereby increasing cellular penetration of the cyclic dimer peptides into various cell types. Further, in at least one embodiment a noncovalent bond is provided between a cyclic dimer peptide of the present invention and a permeation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancer reduces peptide aggregation and increasing stability and solubility for the cyclic peptide dimer or C-N cyclic peptide monomer or dimer molecule.

(681) Other embodiments of the invention provide a method for treating an individual with a C-N cyclic 47 integrin antagonist monomer or dimer molecule having an increased half-life. In one aspect, the present invention provides an integrin antagonist dimer molecule having a half-life of at least one day in vitro or in vivo (e.g., when administered to a human subject). In one embodiment, the dimer molecule has a half-life of at least three days. In another embodiment, the dimer molecule has a half-life of four days or longer. Further, in another embodiment the dimer molecule has a half-life of eight days or longer. In another embodiment, the dimer molecule is derivatized or modified such that is has a longer half-life as compared to the underivatized or unmodified dimer molecule. In another embodiment, the dimer molecule contains one or more point mutations to increase serum half-life, such as described in WO 00/09560, published Feb. 24, 2000, incorporated herein by reference.

(682) Other embodiments of the invention provide a method for treating an individual with an 47 integrin antagonist cyclic dimer molecule having an increased half-life. In one aspect, the present invention provides an integrin antagonist cyclic dimer molecule having a half-life of at least several hours to one day in vitro or in vivo (e.g., when administered to a human subject) sufficient for daily (q.d.) or twice daily (b.i.d.) dosing of a therapeutically effective amount. In another embodiment, the cyclic dimer molecule has a half-life of three days or longer sufficient for weekly (q.w.) dosing of a therapeutically effective amount. Further, in another embodiment the cyclic dimer molecule has a half-life of eight days or longer sufficient for bi-weekly (b.i.w.) or monthly dosing of a therapeutically effective amount. In another embodiment, the cyclic dimer molecule is derivatized or modified such that is has a longer half-life as compared to the underivatized or unmodified dimer molecule. In another embodiment, the cyclic dimer molecule contains one or more chemical modifications to increase serum half-life.

(683) When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form. By a therapeutically effective amount of the compound of the invention is meant a sufficient amount of the compound to treat an integrin-related disease, (for example, to reduce inflammation associated with IBD) at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

(684) Alternatively, a cyclic dimer compound or C-N cyclic compound of the present invention may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The compositions may be administered parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), rectally, or bucally. The term parenteral as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

(685) Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

(686) These cyclic dimer or C-N cyclic monomer or dimer compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

(687) Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

(688) The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

(689) Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical lung administration, including those for inhalation and intranasal, may involve solutions and suspensions in aqueous and non-aqueous formulations and can be prepared as a dry powder which may be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter. Suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

(690) Alternatively, the cyclic dimer compositions and C-N cyclic monomer or dimer compositions may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant. The liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent. The pressurized cyclic dimer or C-N cyclic monmer or dimer composition may also contain a surface active agent, such as a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.

(691) A further form of topical administration is to the eye. A cyclic dimer compound or a C-N cyclic monomer or dimer compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/ciliary, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material. Alternatively, the compounds of the invention may be injected directly into the vitreous and aqueous humour.

(692) Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

(693) Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present cyclic dimer or C-N cyclic monomer or dimer compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art.

(694) Total daily dose of the cyclic dimer or C-N cyclic monomer or dimer compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily and more usually 1 to 300 mg/kg body weight.

(695) Non-Invasive Detection of Intestinal Inflammation

(696) The cyclic dimer peptides and the C-N cyclic monomer and dimer peptides of the invention may be used for detection, assessment and diagnosis of intestinal inflammation by microPET imaging using an orally stable compound having subunits selected from and corresponding to SEQ ID NOs: 1-146, and of formulas (I), (II), (III), or (IV) or any other cyclic peptide or C-N cyclic peptide of the present invention, that is further labeled with at least one of a chelating group and a detectable label as part of a non-invasive diagnostic procedure. In one embodiment, a C-N cyclic integrin antagonist monomer or dimer molecule or integrin antagonist cyclic dimer peptide is conjugated with a bifunctional chelator to provide an orally stable C-N cyclic molecule. In another embodiment, a C-N cyclic integrin antagonist or integrin antagonist cyclic dimer peptide molecule is radiolabeled to provide an orally stable molecule. The orally stable, chelated or radiolabeled molecule is then administered to a subject orally or rectally. In one embodiment, the orally stable dimer molecule is included in drinking water. Following uptake of the dimer molecules, microPET imaging may be used to visualize inflammation throughout the subject's bowels and digestive track.

EXAMPLES

Example 1

Synthesis of Cyclic Dimer Peptide Compounds

(697) Cyclic peptide dimers of the present invention were synthesized as described below for one representative peptide.

(698) Peptide Sequence Assembly

(699) The monomer peptide sequence (Ac-k(IvDde)-Pen(Acm)-MeR-S-D-T-L-Pen(Acm)-W-k(NH2)) was assembled by standard solid phase peptide synthesis techniques. (2.0 eq amino acid coupling, coupling reagents 0.20M HBTU/DIEA in DMF, and Fmoc deprotection using a solution of 20/80 piperidine/DMF). For MeR and Pen(Acm) coupling, double coupling of 2.0 eq amino acid, 2.0 eq PyAOP, and 4 eq DIEA in DMF were used (Fmoc-Pen(Acm)-OH (2 eq), PyAOP (2 eq), DIEA (4 eq) in DMF, allowed to react for 1 hr. After an hour, added additional 1.0 eq PyAOP and allowed to react for another hr. Check the reaction by Chloranil test, when the reaction completed, removed Fmoc and couple k(IvDde) and capped with acetic anhydride.

(700) Cleavage and Isolation of Monomer

(701) To cleave the monomer peptide from the resin and to remove side chain protecting groups on the peptide, the protected peptide resin was treated with a cleavage solution containing TFA:water:DODT:TIPS (90v:5v:2.5v:2.5v). The cleavage reaction mixture was stirred for 2.0 h at room temperature. The spent resin was filtered off. The filtrate was then precipitated into cold ethyl ether and centrifuged to collect the peptide. The ethyl ether was decanted, and the solid precipitate was washed two times with cold ethyl ether. TFA cleavage of this peptide resin resulted in a peptide with an Acm-protected Pen (both Pen) and k(IvDde) on the N-terminal.

(702) The unpurified monomer was analyzed by RP-HPLC Method 5-50-20 min at 50 C (Phenomenex Aeris peptide C18 1504.6 mm, 3.6 micron) MPA: 0.1% TFA in water and MPB: 0.1% TFA in ACN). LC/MS was performed to verify the expected molecular weight of the linear monomer.

(703) Disulfide Bond Formation Pen(Acm)

(704) The unpurified linear monomer, was dissolved in 50:50 ACN:water then diluted to 20:80 ACN:water (concentration 1 mg/mL) and oxidized with I2/Me0H (Methanol) solution until the color is dark yellow. When the yellow color fades out, added additional I2/Me0H solution until the reaction mixture stays dark yellow to amber color (cyclization time takes around 30 min). The reaction was monitored using LCMS. The reaction was quenched with ascorbic acid when complete, until a colorless solution was obtained. The completed reaction mixture was diluted down to 10% ACN and purified.

(705) The unpurified cyclized monomer was analyzed by RP-HPCL Method 5-50-20 min at 50 C (Phenomenex Aeris peptide C18 1504.6 mm, 3.6 micron), MPA: 0.1% TFA in water and MPB: 0.1% TFA in ACN). LC/MS was performed to verify the expected molecular weight of the linear monomer.

(706) Purification of Cyclized Monomer

(707) The cyclized monomer was purified on a preparative RP-HPLC system using the following conditions: Buffer A: 0.1% TFA in water and Buffer B: 0.1% TFA in ACN. Fractions were collected and analyzed by analytical HPLC. Fractions of purity >90% combined for dimerization.

(708) The purified monomer was analyzed by RP-HPLC Method 5-50-20 min at 50 C (Phenomenex Aeris peptide C18 1504.6 mm, 3.6 micron), MPA: 0.1% TFA in water and MPB: 0.1% TFA in ACN). LC/MS was performed to verify the expected molecular weight of the linear monomer.

(709) Linker Activation and Dimerization

(710) Small Scale DIG Linker Activation Procedure:

(711) 5 mL of NMP was added to a glass vial containing IDA diacid (304.2 mg, 1 mmol), N-hydroxysuccinimide (NHS, 253.2 mg, 2.2 eq. 2.2 mmol) and a stirring bar. The mixture was stirred at room temperature to completely dissolve the solid starting materials. N, N-Dicyclohexylcarbodiimide (DCC, 453.9 mg, 2.2 eq., 2.2 mmol) was then added to the mixture. Precipitation appeared within 10 min and the reaction mixture was further stirred at room temperature overnight. The reaction mixture was then filtered to remove the precipitated dicyclohexylurea (DCU). The activated linker was kept in a closed vial prior to use for dimerization. The nominal concentration of the activated linker was approximately 0.20 M.

(712) Monomer Dimerization (C-Terminal Dimerization)

(713) The pure monomer was converted to the corresponding dimer by titrating in 0.45 eq (0.4 eq, then 0.05 eq) of 0.1M DIG linker to the monomeric peptide in 5.0 eq DIEA in DMF. Coupling reaction took approximately 30 min under ambient conditions. The reaction was monitored using HPLC and LCMS. Upon completion, 5% of Hydrazine hydrate (v/v) was added to the reaction to remove the IvDde protecting group from N-terminal D-Lys. After 30 min, the reaction was monitored by LCMS, upon completion the reaction was diluted with water and purified.

(714) The crude C-terminal dimer was analyzed by the analytical HPLC Method 5-50-20 min at 50 C (Phenomenex Aeris peptide C18 1504.6 mm, 3.6 micron), MPA: 0.1% TFA in water and MPB: 0.1% TFA in ACN). LC/MS was used to verify the expected molecular weight of the dimerC-terminal dimer purification

(715) The crude C-terminal dimer was purified on a preparative RP-HPLC system using the following conditions: Buffer A: 0.1% TFA in water and Buffer B: 0.1% TFA in ACN, Phenomenex Luna 101A C18 25021.2 mm column with a flow rate of 20 mL/min, using a 20:50:45 min gradient (20% B to 50% B in 50 min). Fractions were collected and analyzed by analytical HPLC Method 5-50-20 min and lyophilized. Fractions with purity >90 Area-% were combined for N-terminal dimerization.

(716) N-Terminal Dimerization

(717) The pure C-terminal dimer was converted to the corresponding cyclic (N and C-terminal) dimer by titrating in 0.45 eq (0.4 eq, then 0.05 eq) of 0.1M DIG linker to the monomeric peptide in 5.0 eq DIEA in DMSO (1 mg/mL concentration). Dimerization reaction took approximately 45 min under ambient conditions. After 45 min, the reaction was monitored by LCMS, upon completion the reaction was diluted with water and purified.

(718) The crude cyclic dimer was analyzed by the analytical HPLC Method 5-50-20 min at 50 C (Phenomenex Aeris peptide C18 1504.6 mm, 3.6 micron), MPA: 0.1% TFA in water and MPB: 0.1% TFA in ACN). LC/MS was used to verify the expected molecular weight of the cyclic dimer.

(719) Cyclic (N and C-Terminal) Dimer Purification

(720) The crude cyclic dimer was purified on a preparative RP-HPLC system using the following conditions: Buffer A: 0.1% TFA in water and Buffer B: 0.1% TFA in ACN, Phenomenex Luna 101A C18 25021.2 mm column with a flow rate of 20 mL/min, using a 20:50:45 min gradient (20% B to 50% B in 50 min). Fractions were collected and analyzed by analytical HPLC Method 5-50-20 min and lyophilized. Fractions with purity >95 Area-% were combined as a final product.

(721) Purification

(722) Analytical reverse-phase, high performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm250 mm) (Phenomenex). Semi-Preparative reverse phase HPLC was performed on a Gemini 10 [tm C18 column (22 mm250 mm) (Phenomenex) or Jupiter 10 [tm, 300 A C.18 column (21.2 mm250 mm) (Phenomenex). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 15 mL/min (preparative). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 15 mL/min (preparative).

(723) Linker Activation and Dimerization

(724) Small Scale DIG Linker Activation Procedure:

(725) 5 mL of NMP was added to a glass vial containing IDA diacid (304.2 mg, 1 mmol), N-hydroxysuccinimide (NHS, 253.2 mg, 2.2 eq. 2.2 mmol) and a stirring bar. The mixture was stirred at room temperature to completely dissolve the solid starting materials. N, N-Dicyclohexylcarbodiimide (DCC, 453.9 mg, 2.2 eq., 2.2 mmol) was then added to the mixture. Precipitation appeared within 10 min and the reaction mixture was further stirred at room temperature overnight. The reaction mixture was then filtered to remove the precipitated dicyclohexylurea (DCU). The activated linker was kept in a closed vial prior to use for dimerization. The nominal concentration of the activated linker was approximately 0.20 M.

(726) For dimerization using PEG linkers, there is no pre-activation step involved. Commercially available pre-activated bi-functional PEG linkers were used.

(727) Dimerization Procedure:

(728) 2 mL of anhydrous DMF was added to a vial containing C-N cyclic peptide monomer (0.1 mmol). The pH of the peptide was the adjusted to 8-9 with DIEA. Activated linker (IDA or PEG13, PEG 25) (0.48 eq relative to monomer, 0.048 mmol) was then added to the C-N cyclic monomer solution. The reaction mixture was stirred at room temperature for one hour. Completion of the dimerization reaction was monitored using analytical HPLC. The time for completion of dimerization reaction varied depending upon the linker After completion of reaction, the C-N cyclic peptides were precipitated in cold ether and centrifuged. The supernatant ether layer was discarded. The precipitation step was repeated twice. The crude dimer was then purified using reverse phase HPLC (Luna C 18 support, 10 u, 100 A, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient of 15% B and change to 45% B over 60 min, flow rate 15 ml/min). Fractions containing pure dimerized product were then freeze-dried on a lyophilyzer.

Example 2

Characterization of Cyclic Peptide Compounds

(729) The stability, potency, and selectivity of certain peptide dimers is demonstrated.

(730) Simulated Intestinal Fluid (SIF) Stability Assay

(731) Studies are carried out in simulated intestinal fluid (SIF) to evaluate intestinal stability of the dimer molecules of the instant invention. To prepare the SIF reagent, blank FASSIF is prepared by dissolving 0.348 g NaOH, 3.954 g sodium phosphate monobasic monohydrate and 6.186 g NaCl in a final volume of 1 liter water (final pH=6.5). To this solution, 24 g porcine pancreatin (Sigma catalog P7545) is added and stirred for 30 minutes (final pancreatin concentration is 2.4%). The solution is filtered through a cheese cloth and a No. 1 Whatman filter, and 10 ml aliquots are stored at 70 C. To run the reaction, a 10 ml aliquot is thawed at 37 C. and 1250 aliquots are removed and mixed with an equal volume of blank FASSIF. The peptide stock solution (10 mM in 100% DMSO) is diluted 75-fold in blank FASSIF. A 500 aliquot of the diluted peptide is combined with 125 l pancreatin (2.4%) and 1250 blank FASSIF to yield final concentrations of 1% pancreatin and 22 M peptide. The reactions are incubated at 37 C., and at various time points 500 aliquots are removed and added to 2000 of quench solution containing 50% acetonitrile, 50% methanol, 5% formic acid, and 1 g/ml internal standard. The quenched samples are centrifuged at 10,000 rpm for 10 minutes, and the supernatants analyzed by LCMS/MS. The percent remaining at each time point are calculated based on the peak area response ratio of test to compound to internal standard. Half-lives are calculated by fitting to a first-order exponential decay equation using GraphPad.

(732) 47-MAdCAM Competition ELISA

(733) A nickel coated plate (Pierce #15442) is coated with rh integrin 47 (R&D Systems #5397-A30) at 800 ng/well and incubated at room temperature with shaking for 1 hr. The solution iss then remove by shaking and blocked with assay buffer (50 mM Tris-HCl pH7.6, 150 mM NaCl, 1 mM MnCl.sub.2 or MgCl.sub.2, 0.05% Tween-20 and 0.5% BSA) at 250 ul/well. The plate was then incubated at room temperature for 1 hr. Each well was washed 3 times with wash buffer (50 mM Tris-HCl pH7.6, 100 mM NaCl, 1 mM MnCl.sub.2 or MgCl.sub.2, 0.05% Tween-20). To each well was added 25 ul of a serial dilution (3-fold dilutions in assay buffer) of peptides starting at 20 M. 25 ul of recombinant human MAdCAM-1 (R&D Systems #6056-MC) was then added to each well at a fixed concentration 20 nM. The final starting peptide concentration was 10 M, and the final MAdCAM-1 concentration was 10 nM. The plates were then incubated at room temperature for 1 hr to reach binding equilibrium. The wells were then washed three times with wash buffer. 50 ul of mouse antihuman IgG1-HRP (Invitrogen # A10648) diluted in 1:2000 in assay buffer was then added to each well. The wells are incubated at room temperature for 45 min with shaking. The wells were then washed 3 times with wash buffer. 100 ul of TMB were then added to each well and closely observe during development time. The reaction was stopped with 2N H.sub.2SO.sub.4 and absorbance was read at 450 nm.

(734) 41-VCAM Competition ELISA

(735) A Nunc MaxiSorp plate was coated with rh VCAM-1/CD106 Fc chimera (R&D #862-VC) at 400 ng/well in 50 ul per well in 1PBS and incubated overnight at 4 C. The solution was removed by shaking and then blocked with 250 ul of 1% BSA in 1PBS per well. The wells were then incubated at room temperature for 1 hr with shaking. Each well was then washed once with wash buffer (50 mM Tris-HCl pH7.6, 100 mM NaCL, 1 mM MnCl.sub.2 or MgCl.sub.2, 0.05% Tween-20). 25 ul of serial dilutions of peptides starting at 200 M in assay buffer (Assay buffer: 50 mM Tris-HCl pH7.6, 100 mM NaCl, 1 mM MgCl.sub.2 or MgCl.sub.2, 0.05% Tween-20) was added to each well. Additionally, 25 ul of 41 (R&D Systems #5668 A4) was added to each well at a fixed concentration of 120 nM. The final peptide and 41 concentrations were 100 M and 60 nM, respectively. The plates were then incubated at 37 C. for 2 hr. The solution was then removed by shaking and each well was washed three times with wash buffer. 50 ul of 9F10 antibody at 4 ug/ml (purified mouse anti-human CD49d, BD Bioscience Cat#555502) was then added to each well, and the plate was incubated at room temperature for 1 hr with shaking. The solution was again removed by shaking, and each well was washed three times with wash buffer. 50 ul of peroxidase conjugated AffiniPure Goat anti-mouse IgG (Jackson immune research cat #115-035-003) diluted in 1:5000 in assay buffer was added to each well. The plate was incubated at room temperature for 30 min with shaking. Each well was then washed 3 times with wash buffer. 100 ul of TMB was then added to each well and closely observe during developing time. The reaction was stepped with 2N H.sub.2SO.sub.4 and absorbance was read at 450 nm.

(736) 47-MAdCAM Cell Adhesion Assay

(737) RPMI 8866 cells (Sigma #95041316) are cultured in RPMI 1640 HEPES medium (Invitrogen #22400-089) supplemented with 10% serum (Fetal Bovine Serum, Invitrogen #16140-071), 1 mM sodium pyruvate (Invitrogen #11360-070), 2 mM L-glutamine (Invitrogen #25030-081) and Penicillin-Streptomycin (Invitrogen #15140-122) at 100 units of penicillin and 100 lug of streptomycin per ml. The cells are washed two times in DMEM medium (ATCC #30-2002) supplemented with 0.1% BSA, 10 mM HEPES pH 7 and 1 mM MnCl.sub.2. The cells are re-suspended in supplemented DMEM medium at a density of 410.sup.6 cells/ml.

(738) A Nunc MaxiSorp plate was coated with rh MAdCAM-1/Fc Chimera (R&D #6065-MC) at 200 ng per well in 50 ul per well in 1PBS and incubated at 4 C. overnight. The solution was then removed by shaking, blocked with 250 ul per well PBS containing 1% BSA, and incubated at 37 C. for 1 hr. The solution was removed by shaking. Peptides are diluted by serial dilution in a final volume of 50 ul per well (2 concentration). To each well, 50 ul of cells (200,000 cells) are added and the plate is incubated at 37 C., 5% CO.sub.2 for 30-45 min to allow cell adhesion. The wells are washed manually three times (100 ul per wash) with supplemented DMEM. After the final wash, 100 ul/well of supplemented DMEM and 10 ul/well of MTT reagent (ATTC cat#30-1010K) are added. The plate is incubated at 37 C., 5% CO2 for 2-3 hrs until a purple precipitate is visible. 100 ul of Detergent Reagent (ATTC cat#30-1010K) is added to each well. The plate is covered from the light, wrapped in Parafilm to prevent evaporation, and left overnight at room temperature in the dark. The plate is shaken for 5 min and the absorbance at 570 nm is measured. To calculate the dose response, the absorbance value of control wells not containing cells is subtracted from each test well.

(739) 41-VCAM Cell Adhesion Assay

(740) Jurkat E6.1 cells (Sigma #88042803) are cultured in RPMI 1640 HEPES medium (Invitrogen #22400-089) supplemented with 10% serum (Fetal Bovine Serum, Invitrogen #16140-071), 1 mM sodium pyruvate (Invitrogen #11360-070), 2 mM L-glutamine (Invitrogen #25030-081) and Penicillin-Streptomycin (Invitrogen #15140-122) at 100 units of penicillin and 100 g of streptomycin per ml. The cells are washed two times in DMEM medium (ATCC #30-2002) supplemented with 0.1% BSA, 10 mM HEPES pH 7 and 1 mM MnCl.sub.2. The cells are re-suspended in supplemented DMEM medium at a density of 410.sup.6 cells/ml.

(741) A Nunc MaxiSorp plate was coated with rh VCAM-1/CD106 Fc chimera (R&D #862-VC) at 400 ng per well in 50 ul per well in 1PBS and incubated at 4 C. overnight. The solution was then removed by shaking, blocked with 250 ul per well PBS containing 1% BSA, and incubated at 37 C. for 1 hr. The solution was removed by shaking. Peptides are diluted by serial dilution in a final volume of 50 ul per well (2 concentration). To each well, 50 ul of cells (200,000 cells) are added and the plate is incubated at 37 C., 5% CO.sub.2 for 30-45 min to allow cell adhesion. The wells are washed manually three times (100 ul per wash) with supplemented DMEM. After the final wash, 100 ul/well of supplemented DMEM and 10 ul/well of MTT reagent (ATTC cat#30-1010K) are added. The plate is incubated at 37 C., 5% CO2 for 2-3 hrs until a purple precipitate is visible. 100 ul of Detergent Reagent (ATTC cat#30-1010K) is added to each well. The plate is covered from the light, wrapped in Parafilm to prevent evaporation, and left overnight at room temperature in the dark. The plate is shaken for 5 min and the absorbance at 570 nm is measured. To calculate the dose response, the absorbance value of control wells not containing cells is subtracted from each test well.

(742) Data generated from an illustrative set of cyclic peptides of the invention is shown in the figures.

Example 3

Synthesis of C-N Cyclic Peptide Compounds

(743) Synthesis of Peptide Subunits

(744) The monomer peptide subunits of the present invention may be synthesized by many techniques that are known to those skilled in the art. Novel and unique monomer subunits were synthesized, purified, and dimerized using the techniques provided herein.

(745) The C-N cyclic peptides subunits of the present invention were synthesized using the Merrifield solid phase synthesis techniques on Protein Technology's Symphony multiple channel synthesizer. The C-N cyclic peptides were assembled using HBTU (0-Benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluoro-phosphate), Diisopropylethylamine(DIEA) coupling conditions. Rink Amide MBHA resin 100-200 mesh, 0.57 mmoUg, is used for peptides with C-terminal amides and pre-loaded Wang Resin with Na-Fmoc protected amino acid is used for peptides with C-terminal acids. The coupling reagents (HBTU and DIEA premixed) were prepared at 100 mmol concentration. Similarly amino acids solutions were prepared at 100 mmol concentration. The peptides were assembled using standard Symphony protocols.

(746) Assembly

(747) The peptide sequences were assembled as follows: Resin (250 mg, 0.14 mmol) in each reaction vial was washed twice with 4 ml of DMF followed by treatment with 2.5 ml of 20% 4-methyl piperidine (Fmoc de-protection) for 10 min. The resin was then filtered and washed two times with DMF (4 ml) and re-treated with N-methyl piperifine for additional 30 minute. The resin was again washed three times with DMF (4 ml) followed by addition 2.5 ml of amino acid and 2.5 ml of HBTU.sup.-DIEA mixture. After 45 min of frequent agitations, the resin was filtered and washed three timed with DMF (4 ml each). For a typical peptide of the present invention, double couplings were performed for first 25 amino acid, and triple couplings were performed for the remaining residues. After completing the coupling reaction, the resin was washed three times with DMF (4 ml each) before proceeding to the next amino acid coupling.

(748) Cleavage

(749) Following completion of the peptide assembly, the peptide was cleaved from the resin by treatment with cleavage reagent, such as reagent K (82.5% trigluoroacetic acid, 5% water, 5% thioanisole, 5% phenol, 2.5% 1,2-ethanedithiol). The cleavage reagent was able to successfully cleave the peptide from the resin, as well as all remaining side chain protecting groups.

(750) The cleaved were precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off and a second aliquot of cold ether was added, and the procedure repeated. The crude peptide was dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered. The quality of linear peptide was then verified using electrospray ionization mass spectrometry (ESI-MS) (Micromass/Waters ZQ) before being purified.

(751) Oxidation

(752) 50 mg of crude, cleaved peptide was dissolved in 20 ml of water:acetonitrile. Saturated Iodine in acetic acid was then added drop wise with stirring until yellow color persisted. The solution was stirred for 15 minutes and the reaction was monitored with analytic HPLC and LCMS. When the reaction was completed, solid ascorbic acid was added until the solution became clear. The solvent mixture was then purified by first being diluted with water and then loaded onto a reverse phase HPLC machine (Luna C18 support, 10 u, 100 A, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, and changed to 50% B over 60 minutes at a flow rate of 15 ml/min). Fractions containing pure product were then freeze-dried on a lyophilyzer.

(753) C-N Cyclization

(754) The peptide monomers were cyclized using known methods for C to N cyclization using standard coupling reagents.

(755) Purification

(756) Analytical reverse-phase, high performance liquid chromatography (HPLC) was performed on a Gemini C18 column (4.6 mm250 mm) (Phenomenex). Semi-Preparative reverse phase HPLC was performed on a Gemini 10 [tm C18 column (22 mm250 mm) (Phenomenex) or Jupiter 10 m, 300 A C.18 column (21.2 mm250 mm) (Phenomenex). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 15 mL/min (preparative). Separations were achieved using linear gradients of buffer B in A (Mobile phase A: water containing 0.15% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA), at a flow rate of 1 mL/min (analytical) and 15 mL/min (preparative).

Example 4

Characterization of C-N Cyclic Peptide Compounds

(757) The stability, potency, and selectivity of certain peptide dimers is demonstrated. SIF stability assay, 47-MAdCAM Competition ELISA, 41-VCAM Competition ELISA, 47-MAdCAM Cell Adhesion Assay, 41-VCAM Cell Adhesion Assay, is performed as described above.

(758) Data generated from an illustrative set of C-N cyclic peptides of the invention is shown in FIG. 8.

(759) The present invention may be embodied in other specific forms without departing from its structures, methods, or other essential characteristics as broadly described herein and claimed hereinafter. The described embodiments are to be considered in all respects only as illustrative, and not restrictive. The scope of the invention is, therefore, indicated by the appended claims, rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Cyclic monomer and dimer peptides having integrin antagonist activity

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Abstract

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Description