The present invention is related to the use of HMGB1 antagonists such as K883 in the treatment and/or prevention and/or inhibition of severe sepsis in mammals, e.g., humans, and pharmaceutical compositions for the same comprising HMGB1 antagonists in an effective amount to treat and/or prevent and/or inhibit this condition.

Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.

Disclosed are peptide and peptidomimetic compounds generally according to formula (I) that are useful as GHRP analogs:

R.sup.1-A.sup.1-A.sup.2-A.sup.3-A.sup.4-A.sup.5-R.sup.2   (I)

wherein: A.sup.1 is Aib, Apc or Inp; A.sup.2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A.sup.3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A.sup.4 is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); A.sup.5 is Apc, Dab, Dap, Lys, Orn, or deleted; R.sup.1 is hydrogen, (C1-6)alkyl, (C5-14)aryl, (C1-6)alkyl(C5-14)aryl, (C3-8)cycloakyl, or (C2-10)acyl; and R.sup.2 is OH or NH.sub.2;
and pharmaceutical compositions and methods of use thereof.

The present invention is related to the use of HMGB1 antagonists in the treatment and/or prevention and/or inhibition of acute lung injury in mammals, e.g., humans, and pharmaceutical compositions for the same comprising HMGB1 antagonists, in particular K883, in an effective amount to treat and/or prevent and/or inhibit this condition.

The present invention addresses the problem of providing an inhibitor which has an excellent inhibitory activity on a p21-activated kinase. The present invention, by which has been solved the above-mentioned problem, is a p21-activated kinase 1 inhibitor containing, as an active ingredient, one or more compounds selected from the group consisting of dehydrokawain compounds, derivatives of dehydrokawain compounds, mimosine, derivatives of mimosine, and cucurbitacin compounds.

Racemization-free methods are disclosed for the synthesis of carfilzomib. Novel intermediates and methods of making carfilzomib employing fragment condensation using the novel intermediates are disclosed. Amorphous carfilzomib and methods of making same are disclosed.

The invention provides a method for treating one or more complications of diabetes in a mammal. The method comprises administering to a mammal in need thereof an effective amount of an aromatic-cationic peptide having at least one net positive charge; a minimum of four amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p.sub.m) and the total number of amino acid residues (r) wherein 3 p.sub.m is the largest number that is less than or equal to r+1; and a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p.sub.t) wherein 2a is the largest number that is less than or equal to p.sub.t+1, except that when a is 1, p.sub.t may also be 1.

The invention provides compounds and methods, for example, to carry out organocatalytic Michael additions of aldehydes to cyclically constrained nitroethylene compounds catalyzed by a proline derivative to provide cyclically constrained α-substituted-γ-nitro-aldehydes. The reaction can be rendered enantioselective when a chiral pyrrolidine catalyst is used, allowing for Michael adducts in nearly optically pure form (e.g., 96 to >99% e.e.). The Michael adducts can bear a single substituent or dual substituents adjacent to the carbonyl. The Michael adducts can be efficiently converted to cyclically constrained protected γ-amino acid residues, which are essential for systematic conformational studies of γ-peptide foldamers. New methods are also provided to prepare other γ-amino acids and peptides. These new building blocks can be used to prepare foldamers, such as α/γ-peptide foldamers, that adopt specific helical conformations in solution and in the solid state.

Novel methods for preparation of Carfilzomib and intermediates thereof with high stereo selection are reported. The synthetic procedures result in substantially pure Carfilzomib (I).

##STR00001##

A Gadd45β/MKK7 inhibitor for use in a method of treating a resistant haematological malignancy, combinations of said inhibitor with a further anti-cancer agent and related methods of use.