(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 α-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

被引：111

作者：

Edmondson, Scott D. ^{[1
]}

Mastracchio, Anthony ^{[1
]}

Mathvink, Robert J. ^{[1
]}

He, Jiafang ^{[1
]}

Harper, Bart ^{[1
]}

Park, You-Jung ^{[1
]}

Beconi, Maria ^{[1
]}

Di Salvo, Jerry ^{[1
]}

Eiermann, George J. ^{[1
]}

He, Huaibing ^{[1
]}

Leiting, Barbara ^{[1
]}

Leone, Joseph F. ^{[1
]}

Levorse, Dorothy A. ^{[1
]}

Lyons, Kathryn ^{[1
]}

Patel, Reshma A. ^{[1
]}

Patel, Sangita B. ^{[1
]}

Petrov, Aleksandr ^{[1
]}

Scapin, Giovanna ^{[1
]}

Shang, Jackie ^{[1
]}

Roy, Ranabir Sinha ^{[1
]}

Smith, Aaron ^{[1
]}

Wu, Joseph K. ^{[1
]}

Xu, Shiyao ^{[1
]}

Zhu, Bing ^{[1
]}

Thornberry, Nancy A. ^{[1
]}

Weber, Ann E. ^{[1
]}

机构：

[1] Merck & Co Inc, Merck Res Labs, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 12期

关键词：

D O I：

10.1021/jm060015t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：3614 / 3627

页数：14

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