Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (volitinib) as a highly potent and selective mesenchymal-epithelial transition factor (c-Met) inhibitor in clinical development for treatment of cancer

J Med Chem. 2014 Sep 25;57(18):7577-89. doi: 10.1021/jm500510f. Epub 2014 Sep 15.

Abstract

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure-activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery*
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / chemistry
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyrazines / chemistry
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Triazines / chemistry
  • Triazines / pharmacokinetics
  • Triazines / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • 1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyrazoles
  • Triazines
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-met