Design and synthesis of orally available MEK inhibitors with potent in vivo antitumor efficacy

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• 作者：Mark E. Adams ; ^{mark.adams@takedasd.com} ; Michael B. Wallace ; Toufike Kanouni ; Nicholas Scorah ; Shawn M. O&rsquo ; Connell ; Hiroshi Miyake ; Lihong Shi ; Petro Halkowycz ; Lilly Zhang ; Qing Dong^&dagger ;
• 关键词：MEK inhibitor ; Kinase ; Oncology ; Dihydroindolone ; Dihydroindolizinone
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2411-2414
• 文件大小：576 K

摘要

The structure-based design, synthesis, and biological evaluation of two novel series of potent and selective MEK kinase inhibitors are described herein. The elaboration of a lead pyrrole derivative to a bicyclic dihydroindolone core provided compounds with high potency and good drug-like pharmaceutical properties. Further scaffold modification afforded a series of dihydroindolizinone inhibitors, including an orally available advanced preclinical MEK inhibitor with potent in vivo antitumor efficacy.