(2S, 3S)-3-Amino-4-( 3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide: A selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

摘要

A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2(4-[1,2,4] triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC50 = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.