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
Journal of Medicinal Chemistry2009Vol. 52(5), pp. 1251–1254
Citations Over TimeTop 10% of 2009 papers
Gretchen M. Schroeder, Yongmi An, Zhen‐Wei Cai, Xiaotao Chen, Cheryl M. Clark, Lyndon A. M. Cornelius, Jun Dai, Johnni Gullo-Brown, Ashok Gupta, Benjamin J. Henley, John T. Hunt, Robert Jeyaseelan, Amrita V. 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 Wautlet, Donna Wei, David Williams, Yingru Zhang, Yueping Zhang, Joseph Fargnoli, R. M. Borzilleri
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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