Dipeptidyl peptidase-4 (DPP-4) inhibition is a new generation therapeutic approach to the treatment of type 2 diabetes. Precedent SAR studies of sitagliptin (JanuviaTM) performed to further improve its pharmacological profile demonstrate that the modification of 1,2,4-triazolopiperazine preserve the bioactivity. In an effort to find novel scaffolds as congeners of the 1,2,4-triazolopiperazine of sitagliptin, novel 1,2,3-triazole analogues were designed and efficiently synthesized using Click Chemistry in the key step, and evaluated in vitro. Two 1,2,3-triazole analogues with pyridyl substituent exhibited very promising inhibitory activities. Our results suggest that the position of the nitrogen atom in the pyridine ring might play an important role for the inhibitory activity (p-pyridyl &gt; m-pyridyl &gt; o-pyridyl). To obtain insights into potential binding modes of these analogues in the human DPP-4, we employed computational methods including docking simulations and molecular dynamics simulations. Our computational simulation results are consistent with the bioassay data, and suggest potential binding modes of the analogues in the human DPP-4 and its key amino acid residues for binding the analogues.

Synthesis, evaluation, and computational simulations of novel 1,2,3-triazole analogues of sitagliptin as DPP-4 inhibitors

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.