(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

• Published in: Journal of medicinal chemistry Vol. 49; no. 12; pp. 3614 - 3627
• Main Authors: Edmondson, Scott D., Mastracchio, Anthony, Mathvink, Robert J., He, Jiafang, Harper, Bart, Park, You-Jung, Beconi, Maria, Di Salvo, Jerry, Eiermann, George J., He, Huaibing, Leiting, Barbara, Leone, Joseph F., Levorse, Dorothy A., Lyons, Kathryn, Patel, Reshma A., Patel, Sangita B., Petrov, Aleksandr, Scapin, Giovanna, Shang, Jackie, Roy, Ranabir Sinha, Smith, Aaron, Wu, Joseph K., Xu, Shiyao, Zhu, Bing, Thornberry, Nancy A., Weber, Ann E.
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 15.06.2006
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; AGENT; POTENT; HOMOLOG; DISCOVERY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060015t

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.