(2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine:: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

被引：718

作者：

Kim, D ^{[1
]}

Wang, LP ^{[1
]}

Beconi, M ^{[1
]}

Eiermann, GJ ^{[1
]}

Fisher, MH ^{[1
]}

He, HB ^{[1
]}

Hickey, GJ ^{[1
]}

Kowalchick, JE ^{[1
]}

Leiting, B ^{[1
]}

Lyons, K ^{[1
]}

Marsilio, F ^{[1
]}

McCann, ME ^{[1
]}

Patel, RA ^{[1
]}

Petrov, A ^{[1
]}

Scapin, G ^{[1
]}

Patel, SB ^{[1
]}

Roy, RS ^{[1
]}

Wu, JK ^{[1
]}

Wyvratt, MJ ^{[1
]}

Zhang, BB ^{[1
]}

Zhu, L ^{[1
]}

Thornberry, NA ^{[1
]}

Weber, AE ^{[1
]}

机构：

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 01期

关键词：

D O I：

10.1021/jm0493156

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

引用

页码：141 / 151

页数：11

共 53 条

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