2. Academic Validation
  3. Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series

Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series

  • J Med Chem. 2012 Mar 8;55(5):1868-97. doi: 10.1021/jm201331s.
Longbin Liu 1,  Mark H Norman,  Matthew Lee,  Ning Xi,  Aaron Siegmund,  Alessandro A Boezio,  Shon Booker,  Debbie Choquette,  Noel D D'Angelo,  Julie Germain,  Kevin Yang,  Yajing Yang,  Yihong Zhang,  Steven F Bellon,  Douglas A Whittington,  Jean-Christophe Harmange,  Celia Dominguez,  Tae-Seong Kim,  Isabelle Dussault
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lliu@amgen.com
PMID: 22320327 DOI: 10.1021/jm201331s
Abstract

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.

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