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(2 S ,3 S )-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: A Selective α-Amino Amide Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

2006; American Chemical Society; Volume: 49; Issue: 12 Linguagem: Inglês

10.1021/jm060015t

1520-4804

Scott D. Edmondson, Anthony Mastracchio, Robert J. Mathvink, Jiafang He, Bart Harper, You‐Jung Park, Maria Beconi, Jerry Di Salvo, George J. Eiermann, Huaibing He, Barbara Leiting, Joseph F. Leone, Dorothy Levorse, Kathryn A. Lyons, Reshma A. Patel, Sangita B. Patel, Aleksandr Petrov, Giovanna Scapin, Jackie Shang, Ranabir Sinha Roy, Aaron Smith, Joseph K. Wu, Shiyao Xu, Bing Zhu, Nancy A. Thornberry, Ann E. Weber,

Neuropeptides and Animal Physiology

A series of β-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.