Synthesis, crystal structure, and activity of pyrazole-based inhibitors of p38 kinase

被引：60

作者：

Graneto, Matthew J. ^{[1
]}

Kurumbail, Ravi G. ^{[1
]}

Vazquez, Michael L. ^{[1
]}

Shieh, Huey-Sheng ^{[1
]}

Pawlitz, Jennifer L. ^{[1
]}

Williams, Jennifer M. ^{[1
]}

Stallings, William C. ^{[1
]}

Geng, Lifeng ^{[1
]}

Naraian, Ashok S. ^{[1
]}

Koszyk, Francis J. ^{[1
]}

Stealey, Michael A. ^{[1
]}

Xu, Xiangdong D. ^{[1
]}

Weier, Richard M. ^{[1
]}

Hanson, Gunnar J. ^{[1
]}

Mourey, Robert J. ^{[1
]}

Compton, Robert P. ^{[1
]}

Mnich, Stephen J. ^{[1
]}

Anderson, Gary D. ^{[1
]}

Monahan, Joseph B. ^{[1
]}

Devraj, Rajesh ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, St Louis Labs, Chesterfield, MO 63107 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 23期

关键词：

D O I：

10.1021/jm0611915

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.

引用

页码：5712 / 5719

页数：8

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