Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors

Bioorg Med Chem. 2012 Sep 1;20(17):5169-80. doi: 10.1016/j.bmc.2012.07.007. Epub 2012 Jul 16.

Abstract

A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o with a c-Met IC(50) of 0.022 μM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a molecular modeling study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry
  • Niacinamide / pharmacology
  • Phosphorylation / drug effects
  • 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
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Niacinamide
  • Proto-Oncogene Proteins c-met