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).

doi:10.1021/jm800401t

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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).

Journal of medicinal chemistry - 10 Jul 2008

Liu Longbin, Siegmund Aaron, Xi Ning, Kaplan-Lefko Paula, Rex Karen, Chen April, Lin Jasmine, Moriguchi Jodi, Berry Loren, Huang Liyue, Teffera Yohannes, Yang Yajing, Zhang Yihong, Bellon Steven F, Lee Matthew, Shimanovich Roman, Bak Annette, Dominguez Celia, Norman Mark H, Harmange Jean-Christophe, Dussault Isabelle, Kim Tae-Seong

Abstract excerpt

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...

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PMID: 18553959
DOI: 10.1021/jm800401t

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