Synthesis and evaluation of novel 1-(2-(5-aryl-1,3,4-Thiadiazol-2-Ylamino)acetyl)Pyrrolidine-2-Carbonitrile derivatives for their DPP-4 inhibiting activity

The current therapeutic agents for Type 2 diabetes (like Insulin, Sulphonylureas, Biguanides, α-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 β-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 β-cells. Moreover, DPP-4 inhibitors can also be administered orally. Overall, DPP 4 inhibitors are promising new class of antidiabetics and intense research in this area has resulted in the launch of sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin as new weapon in the arsenal of oral antihyperglycemic agents. 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.