title: Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors.
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 0.022 μM 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.
authors.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.
authors.forename: Dengyou
authors.initials: D
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.forename: Chunpu
authors.initials: C
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.forename: Yinchun
authors.initials: Y
authors.lastname: Ji
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D019859:Proto-Oncogene Proteins c-met