Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]-4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279):: A very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes

被引：39

作者：

Madar, David J. ^{[1
]}

Kopecka, Hana ^{[1
]}

Pireh, Daisy ^{[1
]}

Yong, Hong ^{[1
]}

Pei, Zhonghua ^{[1
]}

Li, Xiaofeng ^{[1
]}

Wiedeman, Paul E. ^{[1
]}

Djuric, Stevan W. ^{[1
]}

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

Fickes, Michael G. ^{[1
]}

Bhagavatula, Lakshmi ^{[1
]}

McDermott, Todd ^{[1
]}

Wittenberger, Steven ^{[1
]}

Richards, Steven J. ^{[1
]}

Longenecker, Kenton L. ^{[1
]}

Stewart, Kent D. ^{[1
]}

机构：

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 21期

关键词：

D O I：

10.1021/jm060777o

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP-IV)) 1.0 nM) and selective (Ki(DPP8) > 30 mu M; Ki(DPP9) > 30 mu M) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

引用

页码：6416 / 6420

页数：5

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