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Discovery of 3 H ‐Imidazo[4,5‐ b ]pyridines as Potent c‐Met Kinase Inhibitors: Design, Synthesis, and Biological Evaluation
Author(s) -
Chen Danqi,
Wang Ying,
Ma Yuchi,
Xiong Bing,
Ai Jing,
Chen Yi,
Geng Meiyu,
Shen Jingkang
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200120
Subject(s) - kinome , chemistry , stereochemistry , kinase , tyrosine kinase , enzyme , structure–activity relationship , in vitro , combinatorial chemistry , computational biology , biochemistry , receptor , biology
Abstract To identify novel c‐Met inhibitors, sequences and crystal structures of the human kinome were analyzed to find interesting hinge binders that have been underexplored within the tyrosine kinase subfamily. Through this study, the imidazolopyridine ring was selected as a novel c‐Met hinge‐binding inhibitor scaffold. A series of derivatives was prepared, and the structure–activity relationships were studied. Among these, one compound in particular showed excellent activities in enzymatic and cellular assays, good in vitro metabolic stability, and favorable pharmacokinetic parameters. When administered orally, the compound inhibited tumor growth in an NIH‐3T3/TPR‐Met xenograft model and did not show adverse effects on body weight. The present work not only conceptually demonstrates a new route for designing novel kinase inhibitors by using known structural information of ligand–hinge interactions but also provides a series of imidazolopyridine derivatives as potent c‐Met inhibitors.