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
Copyright policy )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
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.
- Bristol-Myers Squibb (Germany) Germany
- Bristol-Myers Squibb (United States) United States
Models, Molecular, Dihydropyridines, Pyridones, Administration, Oral, Aminopyridines, Mice, Nude, Antineoplastic Agents, Proto-Oncogene Proteins c-met, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Rats, Mice, Structure-Activity Relationship, Dogs, Solubility, Cell Line, Tumor, Animals, Humans
Models, Molecular, Dihydropyridines, Pyridones, Administration, Oral, Aminopyridines, Mice, Nude, Antineoplastic Agents, Proto-Oncogene Proteins c-met, Crystallography, X-Ray, Xenograft Model Antitumor Assays, Rats, Mice, Structure-Activity Relationship, Dogs, Solubility, Cell Line, Tumor, Animals, Humans
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