2. Academic Validation
  3. 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)

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.
Longbin Liu 1,  Aaron Siegmund,  Ning Xi,  Paula Kaplan-Lefko,  Karen Rex,  April Chen,  Jasmine Lin,  Jodi Moriguchi,  Loren Berry,  Liyue Huang,  Yohannes Teffera,  Yajing Yang,  Yihong Zhang,  Steven F Bellon,  Matthew Lee,  Roman Shimanovich,  Annette Bak,  Celia Dominguez,  Mark H Norman,  Jean-Christophe Harmange,  Isabelle Dussault,  Tae-Seong Kim
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lliu@amgen.com
PMID: 18553959 DOI: 10.1021/jm800401t
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/KDR/Flk-1. 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14723
    98.18%, c-Met/HGFR Inhibitor