Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity

被引：138

作者：

Szczepankiewicz, Bruce G. ^{[1
]}

Kosogof, Christi ^{[1
]}

Nelson, Lissa T. J. ^{[1
]}

Liu, Gang ^{[1
]}

Liu, Bo ^{[1
]}

Zhao, Hongyu ^{[1
]}

Serby, Michael D. ^{[1
]}

Xin, Zhili ^{[1
]}

Liu, Mei ^{[1
]}

Gum, Rebecca J. ^{[1
]}

Haasch, Deanna L. ^{[1
]}

Wang, Sanyi ^{[1
]}

Clampit, Jill E. ^{[1
]}

Johnson, Eric F. ^{[1
]}

Lubben, Thomas H. ^{[1
]}

Stashko, Michael A. ^{[1
]}

Olejniczak, Edward T. ^{[1
]}

Sun, Chaohong ^{[1
]}

Dorwin, Sarah A. ^{[1
]}

Haskins, Kristi ^{[1
]}

Abad-Zapatero, Cele ^{[1
]}

Fry, Elizabeth H. ^{[1
]}

Hutchins, Charles W. ^{[1
]}

Sham, Hing L. ^{[1
]}

Rondinone, Cristina M. ^{[1
]}

Trevillyan, James M. ^{[1
]}

机构：

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

来源：

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

关键词：

D O I：

10.1021/jm060199b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The c-Jun N-terminal kinases ( JNK-1, -2, and -3) are members of the mitogen activated protein ( MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38 alpha, and p38 delta and showed little inhibitory activity against a panel of 74 kinases.

引用

页码：3563 / 3580

页数：18

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