Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors |
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Authors: | Dengyou Zhang Jing Ai Zhongjie Liang Chunpu Li Xia Peng Yinchun Ji Hualiang Jiang Meiyu Geng Cheng Luo Hong Liu |
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Affiliation: | State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China. |
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Abstract: | 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 IC(50) of 0.022μM 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. |
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