Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors

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• 作者：Meng-Hsin Chen ; Patricia Fitzgerald ; Suresh B. Singh ; Edward A. O’ ; Neill ; Cheryl D. Schwartz ; Chris M. Thompson ; Stephen J. O’ ; Keefe ; Dennis M. Zaller ; James B. Doherty
• 关键词：p38 ; MAP Kinase inhibitors
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 March 2008
• 卷：18
• 期：6
• 页码：2222-2226
• 文件大小：148 K

摘要

Synthesis and biological activities of some quinolinone and dihydroquinolinone p38 MAP kinase inhibitors are reported. Modifications to the dihydroquinolinone pharmacophore revealed that dihydroquinolinone may be replaced with a quinolinone pharmacophore and lead to enhanced p38 inhibitory activity. From a study of C-7 substitutions by amino acid side chains, a very potent series of compounds in the p38 enzyme assays was identified. Translation of the in vitro activity into reasonable whole blood activity can be improved in this series of compounds by judicious modification of the physical properties at appropriate regions of the lead.