Discovery of ((4R,5S)-5-amino-4-(2,4,5-trifluorophenyl)cyclohex-1-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

被引：44

作者：

Pei, Zhonghua ^{[1
]}

Li, Xiaofeng ^{[1
]}

von Geldern, Thomas W. ^{[1
]}

Madar, David J. ^{[1
]}

Longenecker, Kenton ^{[1
]}

Yong, Hong ^{[1
]}

Lubben, Thomas H. ^{[1
]}

Stewart, Kent D. ^{[1
]}

Zinker, Bradley A. ^{[1
]}

Backes, Bradley J. ^{[1
]}

Judd, Andrew S. ^{[1
]}

Mulhern, Mathew ^{[1
]}

Ballaron, Stephen J. ^{[1
]}

Stashko, Michael A. ^{[1
]}

Mika, Amanda K. ^{[1
]}

Beno, David W. A. ^{[1
]}

Reinhart, Glenn A. ^{[1
]}

Fryer, Ryan M. ^{[1
]}

Preusser, Lee C. ^{[1
]}

Kempf-Grote, Anita J. ^{[1
]}

Sham, Hing L. ^{[1
]}

Trevillyan, James M. ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Metab Dis Res, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 22期

关键词：

D O I：

10.1021/jm060955d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.

引用

页码：6439 / 6442

页数：4

共 31 条

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