title: Discovery of 3H-imidazo[4,5-b]pyridines as potent c-Met kinase inhibitors: design, synthesis, and biological evaluation.
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.
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors.forename: Danqi
authors.initials: D
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuchi
authors.initials: Y
authors.lastname: Ma
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C575180:1-(4-fluorophenyl)-2-oxo-N-(4-((2-(thiophen-3-yl)-3H-imidazo(4,5-b)pyridin-7-yl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide; D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011728:Pyridones; C029899:imidazole; D019859:Proto-Oncogene Proteins c-met