Discovery of <i>N</i>-(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
Gretchen M. Schroeder(Bristol-Myers Squibb (United States)), Yongmi An(Bristol-Myers Squibb (United States)), Zhen‐Wei Cai(Bristol-Myers Squibb (United States)), Xiaotao Chen(Bristol-Myers Squibb (United States)), Cheryl M. Clark(Bristol-Myers Squibb (United States)), Lyndon A. M. Cornelius(Bristol-Myers Squibb (United States)), Jun Dai(Bristol-Myers Squibb (United States)), Johnni Gullo-Brown(Bristol-Myers Squibb (United States)), Ashok Gupta(Bristol-Myers Squibb (United States)), Benjamin J. Henley(Bristol-Myers Squibb (United States)), John T. Hunt(Bristol-Myers Squibb (United States)), Robert Jeyaseelan(Bristol-Myers Squibb (United States)), Amrita V. Kamath(Bristol-Myers Squibb (United States)), Kyoung Kim(Bristol-Myers Squibb (United States)), Jonathan Lippy(Bristol-Myers Squibb (United States)), Louis J. Lombardo(Bristol-Myers Squibb (United States)), Veeraswamy Manne(Bristol-Myers Squibb (United States)), Simone Oppenheimer(Bristol-Myers Squibb (United States)), John S. Sack(Bristol-Myers Squibb (United States)), Robert J. Schmidt(Bristol-Myers Squibb (United States)), Guoxiang Shen(Bristol-Myers Squibb (United States)), Kevin Stefanski(Bristol-Myers Squibb (United States)), John S. Tokarski(Bristol-Myers Squibb (United States)), George L. Trainor(Bristol-Myers Squibb (United States)), Barri Wautlet(Bristol-Myers Squibb (United States)), Donna Wei(Bristol-Myers Squibb (United States)), David Williams(Bristol-Myers Squibb (United States)), Yingru Zhang(Bristol-Myers Squibb (United States)), Yueping Zhang(Bristol-Myers Squibb (United States)), Joseph Fargnoli(Bristol-Myers Squibb (United States)), R. M. Borzilleri(Bristol-Myers Squibb (United States))
Cited by 277Open Access
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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