Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors

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• 作者：Dengyou Zhang ; Xiaowei Zhang ; Jing Ai ; Yun Zhai ; Zhongjie Liang ; Ying Wang ; Yi Chen ; Chunpu Li ; Fei Zhao ; Hualiang Jiang ; Meiyu Geng ; Cheng Luo ; Hong Liu
• 关键词：Receptor tyrosine kinase ; c-Met ; 2-Amino-5-aryl-3-benzylthiopyridine
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：1 November, 2013
• 年：2013
• 卷：21
• 期：21
• 页码：6804-6820
• 全文大小：4429 K

文摘

A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC₅₀ up to 7.7 nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC₅₀ from 0.19 to 0.71 ¦ÌM) and c-Met activation-mediated cell metastasis. At a dose of 100 mg/Kg, (R)-10b evidently inhibited tumor growth (45 % ) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.