ABSTRACT
The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.
Subject(s)
Enzyme Inhibitors , MAP Kinase Kinase Kinases/antagonists & inhibitors , Pyridines , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Animals , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Furans/chemical synthesis , Furans/chemistry , Furans/pharmacology , Humans , Inhibitory Concentration 50 , MAP Kinase Kinase Kinases/metabolism , Mice , Molecular Structure , Neoplasms/drug therapy , Phosphotransferases/chemistry , Phosphotransferases/metabolism , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Pyridines/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Female , Half-Life , Humans , Hydrogen-Ion Concentration , Mice , Mice, Nude , Mutation , Neoplasms/drug therapy , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.