Discovery of imidazopyridine derivatives as novel c-Met kinase inhibitors: Synthesis, SAR study, and biological activity

Bioorg Chem. 2017 Feb:70:126-132. doi: 10.1016/j.bioorg.2016.12.002. Epub 2016 Dec 19.

Abstract

Receptor tyrosine kinase c-Met acts as an alternative angiogenic pathway in the process and contents of cancers. A series of imidazopyridine derivatives were designed and synthesized according to the established docking studies as possible c-Met inhibitors. Most of these imidazopyridine derivatives displayed nanomolar potency against c-Met in both biochemical enzymatic screens and cellular pharmacology studies. Especially, compound 7g exhibited the most inhibitory activity against c-Met with IC50 of 53.4nM and 253nM in enzymatic and cellular level, respectively. Following that, the compound 7g was docked into the protein of c-Met and the structure-activity relationship was analyzed in detail. These findings indicated that the novel imidazopyridine derivative compound 7g was a potential c-Met inhibitor deserving further investigation for cancer treatment.

Keywords: Cancer; Imidazopyridine derivatives; Molecular docking; c-Met kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Pyridines
  • MET protein, human
  • Proto-Oncogene Proteins c-met