Design and synthesis of novel p38α MAP kinase inhibitors: Discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety

被引：15

作者：

Arai, Tadamasa ^{[1
]}

Ohno, Michihiro ^{[1
]}

Inoue, Hideki ^{[1
]}

Hayashi, Shinnosuke ^{[1
]}

Aoki, Takumi ^{[1
]}

Hirokawa, Hiroe ^{[1
]}

Meguro, Hiroyuki ^{[1
]}

Koga, Yoko ^{[1
]}

Oshida, Keiyu ^{[1
]}

Kainoh, Mie ^{[1
]}

Suyama, Kazuharu ^{[1
]}

Kawai, Hideki ^{[1
]}

机构：

[1] Toray Industries Ltd, Pharmaceut Res Labs, Kamakura, Kanagawa 2488555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 15期

关键词：

Kinase inhibitor; p38; alpha; Pyrazole-benzyl urea; Docking study; Hepatotoxicity; ACTIVATED PROTEIN-KINASE; RHEUMATOID-ARTHRITIS; CROHNS-DISEASE; BIRB-796; AGENTS;

D O I：

10.1016/j.bmcl.2012.05.095

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38 alpha inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38 alpha inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5118 / 5122

页数：5

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