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: mygeng@simm.ac.cn.
5 School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.

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.

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