Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors

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• 作者：Dengyou Zhang ; Jing Ai ; Zhongjie Liang ; Chunpu Li ; Xia Peng ; YinChun Ji ; Hualiang Jiang ; Meiyu Geng ; Cheng Luo ; Hong Liu
• 关键词：Receptor tyrosine kinase ; c-Met ; 2-Aminopyridine-3-carboxamide
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 September, 2012
• 年：2012
• 卷：20
• 期：17
• 页码：5169-5180
• 全文大小：2907 K

文摘

A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o with a c-Met IC₅₀ of 0.022 ¦ÌM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a molecular modeling study.