Improved processes for the preparation of tubulysin compounds, tubulysin drug linker compounds, and their intermediates are disclosed.

Compounds with the following structures ##STR00001##
and their analogs are provided. Compositions that include these structures can be used to inhibit glucose transporters and stop or decrease the proliferation of cancer, treat possible organ rejection and treat autoimmune disease.

The present invention provides processes and compounds for the preparation of glucagon and GLP-1 co-agonist compounds that are useful in the treatment of type 2 diabetes, obesity, nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH).

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 present invention relates to a novel compound and a composition for an anti-diabetes and anti-obesity comprising the same as an active ingredient. The compound or pharmaceutically acceptable salt thereof according to the present invention selectively and specifically acts as an agonist of GPR39, activates the mechanism of glucose-dependent insulin secretion in pancreatic beta cells, and significantly increases glucose tolerance and an anti-diabetic effect, and therefore can be utilized as a composition for improving, preventing, or treating diabetes mellitus. In addition, the compound or pharmaceutically acceptable salt thereof according to the present invention acts on GPR39 so as to have lipolytic ability in adipocytes and adipose tissue, and therefore can be utilized as a composition for improving, preventing, or treating obesity.

Compositions comprising specific tetrapeptides, for use in treating, preventing, minimizing, diminishing or reversing various signs of aging of the skin are provided. The compositions are useful in improving the firmness or elasticity of skin, smoothing of fine-lines or wrinkles, reducing skin pores and hyperpigmentation, and increasing skin thickness, radiance and/or softness.

Systems and methods for treatment of squamous cell carcinoma or other cancer utilizing targeting peptides are described. The targeting peptides interact with SCC cells or other cancerous cells to block or interfere with 14-3-3ε heterodimerization or CDC25A binding to 14-3-3ε. A peptide composition embodiment includes, but is not limited to, at least one of a first targeting peptide comprising a structure of Trp-Tyr-Trp-Lys-NH.sub.2 (SEQ ID NO: 1), a second targeting peptide comprising a structure of phospho-Ser178; Ac-Thr-Gln-Arg-Gln-Asn-Ser-(PO.sub.3.sup.2−)-Ala-Pro-Arg-Met-Leu-Ser-Ser-Asn-NH.sub.2 (SEQ ID NO: 2), and a third targeting peptide comprising a structure of phospho-Thr507 residue; Ac-Arg-Thr-Lys-Ser-Arg-Thr(PO.sub.3.sup.2−)-Trp-Ala-Gly-Glu-Lys-Ser-Lys-Arg-NH.sub.2 (SEQ ID NO: 3).

The present invention generally relates to compounds that are useful for inhibiting one or more trypsin-like S1 serine proteases, HGFA, matriptase, hepsin, KLK5 and/or TMPRSS2 as well as cysteine proteases including trypsin-like cysteine proteases (e.g. Cathepsin B). The present invention also relates to various methods of using the inhibitor compounds to treat or prevent viral infections, including those caused by coronaviruses and influenza, conditions associated with KLK5, various malignancies, pre-malignant conditions, and cancer.

Pharmaceutical compositions comprising specific tetrapeptides, for use in treating, preventing, minimizing, diminishing or reversing degenerative, age-related and trauma-induced disorders, particularly of the eye, are provided.

The invention relates to a compound of general formula (I) as novel inhibitor of blood coagulation factor XIII, methods for synthesis thereof and to use thereof for the prophylaxis or treatment of diseases associated with blood coagulation factor XIII. ##STR00001##