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

  • Eur J Med Chem. 2014 Jun 10:80:254-66. doi: 10.1016/j.ejmech.2014.04.056.
Wei Zhang  1 ,  Jing Ai  2 ,  Dakuo Shi  3 ,  Xia Peng  2 ,  Yinchun Ji  2 ,  Jian Liu  1 ,  Meiyu Geng  4 ,  Yingxia Li  5
Affiliations
  • 1. School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. School of Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 4. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
  • 5. School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: [email protected].
PMID: 24792774 DOI: 10.1016/j.ejmech.2014.04.056
Abstract

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.

Keywords
Kinase inhibitor; Synthesis; c-Met.