Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes

被引：57

作者：

Angell, Richard M. ^{[1
]}

Angell, Tony D. ^{[1
]}

Bamborough, Paul ^{[1
]}

Bamford, Mark J. ^{[1
]}

Chung, Chun-wa ^{[1
]}

Cockerill, Stuart G. ^{[1
]}

Flack, Stephen S. ^{[1
]}

Jones, Katherine L. ^{[1
]}

Laine, Dramane I. ^{[1
]}

Longstaff, Timothy ^{[1
]}

Ludbrook, Steve ^{[1
]}

Pearson, Rosannah ^{[1
]}

Smith, Kathryn J. ^{[1
]}

Smee, Penny A. ^{[1
]}

Somers, Don O. ^{[1
]}

Walker, Ann L. ^{[1
]}

机构：

[1] GlaxoSmithKline R&D, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 15期

关键词：

p38 kinase inhibitors; MAP kinase; biphenyl amide; protein kinase X-ray structure; binding mode; DFG-out; selectivity; kinetics;

D O I：

10.1016/j.bmcl.2008.06.028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The biphenyl amides (BPAs) are a series of p38 alpha MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38 alpha conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4433 / 4437

页数：5

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