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Discovery of 3H-Imidazo[4,5-b]pyridines as Potent c-Met Kinase Inhibitors: Design, Synthesis, and Biological Evaluation

  1. Dr. Danqi Chen1,†,
  2. Ying Wang2,†,
  3. Yuchi Ma1,
  4. Dr. Bing Xiong1,
  5. Dr. Jing Ai2,
  6. Prof. Yi Chen2,
  7. Prof. Dr. Meiyu Geng2,*,
  8. Prof. Dr. Jingkang Shen1,*

Article first published online: 13 MAY 2012

DOI: 10.1002/cmdc.201200120

Issue

ChemMedChem

ChemMedChem

Volume 7, Issue 6, pages 1057–1070, June 2012

Additional Information

How to Cite

Chen, D., Wang, Y., Ma, Y., Xiong, B., Ai, J., Chen, Y., Geng, M. and Shen, J. (2012), Discovery of 3H-Imidazo[4,5-b]pyridines as Potent c-Met Kinase Inhibitors: Design, Synthesis, and Biological Evaluation. ChemMedChem, 7: 1057–1070. doi: 10.1002/cmdc.201200120

Author Information

  1. 1

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

  2. 2

    Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Shanghai, 201203 (P.R. China)

  1. †

    These authors contributed equally to this work.

*Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-tech Park, Shanghai, 201203 (P.R. China)

  1. †

    These authors contributed equally to this work.

Publication History

  1. Issue published online: 25 MAY 2012
  2. Article first published online: 13 MAY 2012
  3. Manuscript Revised: 28 MAR 2012
  4. Manuscript Received: 5 MAR 2012

Funded by

  • Natural Science Foundation of China for Distinguished Young Scholars. Grant Number: 30725046
  • Natural Science Foundation of China for Innovation Research Group. Grant Number: 81021062
  • National Natural Science Foundation of China. Grant Number: 81072580
  • National Science & Technology Major Project. Grant Numbers: 2009ZX09301-001, 2009ZX09501-010

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Keywords:

  • c-Met;
  • kinase inhibitors;
  • imidazolopyridines;
  • structure–activity relationships;
  • hinge binders

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.

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