Discovery of a Potent, Selective, and Orally Bioavailable c-Met Inhibitor: 1-(2-Hydroxy-2-methylpropyl)-<i>N</i>-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (AMG 458) - Concepedia

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Discovery of a Potent, Selective, and Orally Bioavailable c-Met Inhibitor: 1-(2-Hydroxy-2-methylpropyl)-<i>N</i>-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (AMG 458)

DOI Full Paper Access

94

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0

References

2008

Year

Longbin Liu, Aaron Siegmund, Ning Xi, Paula Kaplan‐Lefko, Karen Rex, April Chen, Jasmine Lin, Jodi Moriguchi, Loren Berry, Liyue Huang,

Journal of Medicinal Chemistry

Pharmaceutical ScienceMetabolic Hot SpotChemoprevention StrategyPharmacotherapyAmg 458Pharmaceutical ChemistryTumor BiologyMolecular PharmacologyMedicinal ChemistryAnti-cancer AgentCancer ResearchBiochemistryOncogenic AgentPharmacological AgentDrug DevelopmentPharmacologyTumor MicroenvironmentNatural SciencesRational Drug DesignBioavailable C-met InhibitorInhibited Tumor GrowthMedicineCancer GrowthDrug Discovery

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.