Abstract:
The current therapeutic agents for type 2 diabetes (like Insulin, Sulphonylureas, Biguanides, a-Glucosidase inhibitors, PPAR agonist and GLP-1 agonist), although effective in increasing insulin secretion, are associated with some safety issue and undesirable side effects, including hypoglycemia, abnormalities in cardiovascular responses and ẞ-cell apoptosis. DPP-4 inhibitors offer several potential advantages over existing therapies including decreased risk of hypoglycemia, potential for weight loss and the potential for regeneration and differentiation of pancreatic ẞ-cells. Moreover, DPP-4 inhibitors can also be administered orally. Among all DPP-4 inhibitor derivatives, 2-Cyano pyrrolidine-based inhibitors have been studied most extensively. Apart from behaving as a proline mimic, the presence of the nitrile on the five-membered ring was shown to provide (i) nanomolar inhibition of DPP-4 and (ii) chemical stability adequate for oral administration. These intermediate was fused with 2-amino-5-aryl-1, 3, 4-thiadiazole derivative to get series of novel 1-(2-(5-aryl-1,3,4-thiadiazol-2- ylamino)acetyl)pyrrolidine-2-carbonitrile derivatives. The synthesized DPP-4 inhibitor derivatives were evaluated by fluorescence assay using Gly-Pro-AMC as a DPP-4-specific fluorescent substrate.
