Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458)

J Med Chem. 2008 Jul 10;51(13):3688-91. doi: 10.1021/jm800401t. Epub 2008 Jun 14.

Abstract

Deregulation of the receptor tyrosine kinase c-Met has been implicated in human cancers. Pyrazolones with N-1 bearing a pendent hydroxyalkyl side chain showed selective inhibition of c-Met over VEGFR2. However, studies revealed the generation of active, nonselective metabolites. Blocking this metabolic hot spot led to the discovery of 17 (AMG 458). When dosed orally, 17 significantly inhibited tumor growth in the NIH3T3/TPR-Met and U-87 MG xenograft models with no adverse effect on body weight.

MeSH terms

  • Administration, Oral
  • Aminopyridines / administration & dosage*
  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Aminopyridines / pharmacokinetics
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Design
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Mutation / genetics
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyrazoles / administration & dosage*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Structure-Activity Relationship

Substances

  • 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
  • Aminopyridines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Proto-Oncogene Proteins c-met