Design and Synthesis of DPP 4 Inhibitors and Diabetic Agents

Abstract

Diabetes mellitus is a chronic progressive metabolic disorder that has profound consequences for newlineindividuals, families, and society. To date, main available oral antidiabetic medications target newlineeither insulin resistance (metformin, glitazones), or insulin deficiency (sulfonylureas, glinides), newlinebut leading to shortfalls in medication. Advancement in modern oral hypoglycemic agents may newlinebe encouraged with or in place of traditional therapies. The lower risk for hypoglycemic events newlineas compared with other insulinotropic or insulin-sensitizing agents make DPP-4 inhibitors very newlinepromising candidates for a more physiological treatment of type-2 diabetes. Only some DPP-4 newlineinhibitors are currently used for the treatment of type 2 diabetes (T2DM) and various inhibitors newlinecurrently undergoing animal and human testing. A number of catalytically active DPPs distinct newlinefrom DPP-4 (DPP II, FAP, DPP-8, and DPP-9) have been described that is associated with sideeffect newlineand toxicity. To discover potent and selective and safer drugs in a shorter time frame and newlinewith reduced cost it requires using an innovative approach for designing novel inhibitors. newlineTo design of novel DPP-4 inhibitors ligand based and structure based screening approaches were newlineapplied. An analog based design study was performed using HQSAR, pharmacophore modeling newlineand 3D-QSAR to designing potential lead compounds. For exploration of substrate like and non newlinesubstrate like novel peptidomimatic inhibitors, systematic pharmacophore based screening newlineprotocol was used to screen commercial databases and hits were screened out which were further newlineoptimized and designed new lead compounds. These novel lead compounds were synthesized newlineand evaluate for DPP-4 inhibitory activity. newlineIn-vitro activity assay identified compound SA01, SB08, SC03, SD03 and SD10 are the more newlinecomparable active as with respect to the standard drugs which were further subjected to newlinedetermine invivo hypoglycemic activity. The in vivo studies showed that the compounds newlineexhibited significant reduction in serum glu