Structural chemistry and molecular modeling in the design of DPP4 inhibitors

Abstract

Inhibition of dipeptidyl peptidase IV (DPP-4) is an established approach for the treatment of type 2 diabetes. In 2006, Sitagliptin phosphate, a potent, orally bioavailable and highly selective small molecule DPP-4 inhibitor was approved by the FDA as once daily novel drug for the treatment of type 2 diabetes. Given the clinical success of sitagliptin our laboratories have been interested in generating analogues amenable for once-weekly dosing, to increase medication adherence. The first of such compounds was approved for preclinical and clinical development in 2008. During the back-up development stages, structural chemistry was used to generate new ideas, as well as evaluate in-silico proposals and screening results, and used to guide and significantly accelerate the drug discovery process.