Design, synthesis and activity of a potent, selective series of N-aryl pyridinone inhibitors of p38 kinase

被引：13

作者：

Selness, Shaun R. ^{[1
]}

Boehm, Terri L. ^{[1
]}

Walker, John K. ^{[1
]}

Devadas, Balekudru ^{[1
]}

Durley, Richard C. ^{[1
]}

Kurumbail, Ravi ^{[2
]}

Shieh, Huey ^{[2
]}

Xing, Li ^{[2
]}

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
]}

Devraj, Rajesh V. ^{[1
]}

Messing, Dean ^{[3
]}

Schindler, John F. ^{[4
]}

Hirsch, Jeffrey ^{[4
]}

Saabye, Matthew ^{[4
]}

Bonar, Sheri ^{[4
]}

Webb, Elizabeth ^{[4
]}

Anderson, Gary ^{[4
]}

Monahan, Joseph B. ^{[2
,4
]}

机构：

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

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

[3] Pfizer Corp, Dept Pharmcokinet & Drug Metab, Chesterfield, MO 63017 USA

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 13期

关键词：

p38; kinase; Inflammation; Rheumatoid arthritis; TNF alpha; Pyridinones; RHEUMATOID-ARTHRITIS;

D O I：

10.1016/j.bmcl.2011.04.120

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of N-aryl pyridinone inhibitors of p38 mitogen activated protein (MAP) kinase were designed and prepared based on the screening hit SC-25028 (1) and structural comparisons to VX-745 (5). The focus of the investigation targeted the dependence of potency and metabolic stability on the benzyloxy connectivity, the role of the C-6 position and the substitution pattern on the N-phenyl ring. Further optimization produced the highly selective and potent pyridinones 2 and 3. These inhibitors exhibited activity in both acute and chronic models of inflammation. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4059 / 4065

页数：7

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