Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily

  • J Med Chem. 2009 Mar 12;52(5):1251-4. doi: 10.1021/jm801586s.
Gretchen M Schroeder  1 ,  Yongmi An ,  Zhen-Wei Cai ,  Xiao-Tao Chen ,  Cheryl Clark ,  Lyndon A M Cornelius ,  Jun Dai ,  Johnni Gullo-Brown ,  Ashok Gupta ,  Benjamin Henley ,  John T Hunt ,  Robert Jeyaseelan ,  Amrita Kamath ,  Kyoung Kim ,  Jonathan Lippy ,  Louis J Lombardo ,  Veeraswamy Manne ,  Simone Oppenheimer ,  John S Sack ,  Robert J Schmidt ,  Guoxiang Shen ,  Kevin Stefanski ,  John S Tokarski ,  George L Trainor ,  Barri S Wautlet ,  Donna Wei ,  David K Williams ,  Yingru Zhang ,  Yueping Zhang ,  Joseph Fargnoli ,  Robert M Borzilleri
Affiliations
  • 1. Bristol-Myers Squibb Research and Development, Princeton, New Jersey, 08543-4000, USA. [email protected]
PMID: 19260711 DOI: 10.1021/jm801586s
Abstract

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.

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