title: Discovery and optimization of a series of imidazo[4,5-b]pyrazine derivatives as highly potent and exquisitely selective inhibitors of the mesenchymal-epithelial transition factor (c-Met) protein kinase.
abstract: Aberrant c-Met activation has been implicated in multiple tumor oncogenic processes and drug resistance. In this study, a series of imidazo[4,5-b]pyrazine derivatives was designed and synthesized, and their inhibitory activities were evaluated in vitro. Structure-activity relationship (SAR) was investigated systematically and docking analysis was performed to elucidate the binding mode, leading to the identification of the most promising compound 1D-2 which exhibited significant inhibitory effect on both enzymatic (IC50=1.45nM) and cellular (IC50=24.7nM in H1993 cell line) assays, as well as exquisite selectivity and satisfactory metabolic stability in human and rat liver microsomes.
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
authors.forename: Leduo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
authors.forename: Chen
authors.initials: C
authors.lastname: Shi
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Xia
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China. Electronic address: yujx@sphchina.com.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yu
authors.affiliation: Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd, Building 5, No. 898 Halei Road, Shanghai 201203, PR China. Electronic address: liuyj@sphchina.com.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D019859:Proto-Oncogene Proteins c-met
keywords: Docking study; Imidazo[4,5-b]pyrazines; Structure–activity relationship; c-Met inhibitors