Discovery of novel type II c-Met inhibitors based on BMS-777607

• Published in: European journal of medicinal chemistry 2014-06, Vol.80, p.254-266
• Main Authors: Zhang, Wei, Ai, Jing, Shi, Dakuo, Peng, Xia, Ji, Yinchun, Liu, Jian, Geng, Meiyu, Li, Yingxia
• Format: Article
• Language: English
• Subjects: Aminopyridines - chemistry; Aminopyridines - pharmacology; c-Met; Cell Line, Tumor; Drug Discovery; Humans; Kinase inhibitor; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Pyridones - chemistry; Pyridones - pharmacology; Structure-Activity Relationship; Synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.04.056

Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Compounds bearing a cyclic sulfonamide or α-chloropiperidone scaffold exhibited good activity, which may provide a new basis for further structural optimization. Quinoline-containing analogs exhibited better results than did their counterparts with an aminopyrimidine, aminopyridine, or pyrrolopyridine unit. Two analogs, 22d and 22e, stood out as the most potent c-Met inhibitors with IC50s of 0.9 and 1.7 nM, respectively. These two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies. Twenty-two new analogs based on the structure of BMS-777607 were designed, synthesized, and evaluated to determine their biological activities. Two compounds were more potent than BMS-777607 in enzymatic inhibition and cell proliferation studies. [Display omitted] •Twenty-two analogs based on BMS-777607 were designed and synthesized.•Two analogs were more potent than BMS-777607 in vitro studies.•Novel designed scaffolds may provide a new basis for further optimization.