Novel 6-aminofuro[3,2-c]pyridines as potent, orally efficacious inhibitors of cMET and RON kinases

Bioorg Med Chem Lett. 2013 Aug 1;23(15):4381-7. doi: 10.1016/j.bmcl.2013.05.074. Epub 2013 May 30.

Abstract

A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Female
  • Half-Life
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Mice, Nude
  • Mutation
  • Neoplasms / drug therapy
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • OSI-296
  • Protein Kinase Inhibitors
  • Pyridines
  • Proto-Oncogene Proteins c-met
  • RON protein
  • Receptor Protein-Tyrosine Kinases