Discovery of N-substituted pyridinones as potent and selective inhibitors of p38 kinase

被引：27

作者：

Selness, Shaun R. ^{[1
]}

Devraj, Rajesh V. ^{[1
]}

Monahan, Joseph B. ^{[2
]}

Boehm, Terri L. ^{[1
]}

Walker, John K. ^{[1
]}

Devadas, Balekudru ^{[1
]}

Durley, Richard C. ^{[1
]}

Kurumbail, Ravi ^{[3
]}

Shieh, Huey ^{[3
]}

Xing, Li ^{[3
]}

Hepperle, Michael ^{[1
]}

Rucker, Paul V. ^{[1
]}

Jerome, Kevin D. ^{[1
]}

Benson, Alan G. ^{[1
]}

Marrufo, Laura D. ^{[1
]}

Madsen, Heather M. ^{[1
]}

Hitchcock, Jeff ^{[1
]}

Owen, Tom J. ^{[1
]}

Christie, Lance ^{[1
]}

Promo, Michele A. ^{[1
]}

Hickory, Brian S. ^{[1
]}

Alvira, Edgardo ^{[1
]}

Naing, Win ^{[1
]}

Blevis-Bal, Radhika ^{[1
]}

机构：

[1] Pfizer Corp, Dept Med Chem, Chesterfield, MO 63017 USA

[2] Pfizer Corp, Inflammat Biol, Chesterfield, MO 63017 USA

[3] Pfizer Corp, Struct & Computat Chem, Chesterfield, MO 63017 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 20期

关键词：

p38; kinase; Pyridinones; RHEUMATOID-ARTHRITIS;

D O I：

10.1016/j.bmcl.2009.08.082

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The identification and evolution of a series of potent and selective p38 inhibitors is described. p38 inhibitors based on a N-benzyl pyridinone high-throughput screening hit were prepared and their SAR explored. Their design was guided by ligand bound co-crystals of p38 alpha. These efforts resulted in the identification of 12r and 19 as orally active inhibitors of p38 with significant efficacy in both acute and chronic models of inflammation. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：5851 / 5856

页数：6