Discovery of 3H-imidazo[4,5-b]pyridines as potent c-Met kinase inhibitors: design, synthesis, and biological evaluation

Danqi Chen; Ying Wang; Yuchi Ma; Bing Xiong; Jing Ai; Yi Chen; Meiyu Geng; Jingkang Shen

doi:10.1002/cmdc.201200120

Discovery of 3H-imidazo[4,5-b]pyridines as potent c-Met kinase inhibitors: design, synthesis, and biological evaluation

ChemMedChem. 2012 Jun;7(6):1057-70. doi: 10.1002/cmdc.201200120. Epub 2012 May 13.

Authors

Danqi Chen¹, Ying Wang, Yuchi Ma, Bing Xiong, Jing Ai, Yi Chen, Meiyu Geng, Jingkang Shen

Affiliation

¹ Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.

PMID: 22581753
DOI: 10.1002/cmdc.201200120

Abstract

To identify novel c-Met inhibitors, sequences and crystal structures of the human kinome were analyzed to find interesting hinge binders that have been underexplored within the tyrosine kinase subfamily. Through this study, the imidazolopyridine ring was selected as a novel c-Met hinge-binding inhibitor scaffold. A series of derivatives was prepared, and the structure-activity relationships were studied. Among these, one compound in particular showed excellent activities in enzymatic and cellular assays, good in vitro metabolic stability, and favorable pharmacokinetic parameters. When administered orally, the compound inhibited tumor growth in an NIH-3T3/TPR-Met xenograft model and did not show adverse effects on body weight. The present work not only conceptually demonstrates a new route for designing novel kinase inhibitors by using known structural information of ligand-hinge interactions but also provides a series of imidazolopyridine derivatives as potent c-Met inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design*
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacokinetics
Mice
Mice, Nude
NIH 3T3 Cells
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacokinetics
Structure-Activity Relationship
Transplantation, Heterologous

Substances

1-(4-fluorophenyl)-2-oxo-N-(4-((2-(thiophen-3-yl)-3H-imidazo(4,5-b)pyridin-7-yl)oxy)phenyl)-1,2-dihydropyridine-3-carboxamide
Antineoplastic Agents
Imidazoles
Protein Kinase Inhibitors
Pyridines
Pyridones
imidazole
Proto-Oncogene Proteins c-met