2. Academic Validation
  3. 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

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

Affiliation

  • 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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