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.
MeSH terms
-
Administration, Oral
-
Aminopyridines / chemical synthesis*
-
Aminopyridines / pharmacokinetics
-
Aminopyridines / pharmacology
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / pharmacokinetics
-
Antineoplastic Agents / pharmacology
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Dihydropyridines / chemical synthesis*
-
Dihydropyridines / pharmacokinetics
-
Dihydropyridines / pharmacology
-
Dogs
-
Humans
-
Mice
-
Mice, Nude
-
Models, Molecular
-
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
-
Pyridones / chemical synthesis*
-
Pyridones / pharmacokinetics
-
Pyridones / pharmacology
-
Rats
-
Solubility
-
Structure-Activity Relationship
-
Xenograft Model Antitumor Assays
Substances
-
Aminopyridines
-
Antineoplastic Agents
-
Dihydropyridines
-
N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
-
Pyridones
-
Proto-Oncogene Proteins c-met