Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors

Li Zhang; Beichen Zhang; Jingyun Zhao; Yanle Zhi; Lu Wang; Tao Lu; Yadong Chen

doi:10.1016/j.ejmech.2017.06.057

Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors

Eur J Med Chem. 2017 Sep 29:138:942-951. doi: 10.1016/j.ejmech.2017.06.057. Epub 2017 Jun 29.

Authors

Li Zhang¹, Beichen Zhang¹, Jingyun Zhao¹, Yanle Zhi¹, Lu Wang¹, Tao Lu², Yadong Chen³

Affiliations

¹ Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
² Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: lut163@163.com.
³ Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China. Electronic address: ydchen@cpu.edu.cn.

PMID: 28755635
DOI: 10.1016/j.ejmech.2017.06.057

Abstract

c-Met was emerging as an attractive target for cancer-targeted therapy because deregulation of c-Met has been observed in multiple tumor types. A series of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against MKN45, EBC-1 and PC-3 cell lines. Nine of them showed better activity than lead compound 1 which was found via computer-aided drug design. Among them, compound 8c showed inhibitory activity of 68 nM against c-Met and low micromole cellular potency against MKN45 and EBC-1 cell lines. Moreover, 8c demonstrated more than 50-fold selectivity against other tyrosine kinases tested. The result of western blot indicated that compound 8c was capable of inhibiting the phosphorylation of c-Met kinase in MKN45 cell line in a dose-dependent manner.

Keywords: Cancer; Inhibitors; Synthesis; c-Met; pyrazolo[4,3-c]pyridine.

MeSH terms

Cell Line
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyrazoles
Pyridines
Proto-Oncogene Proteins c-met