ABSTRACT
During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3ß in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidinones/chemistry , Animals , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Mice , Molecular Dynamics Simulation , Neoplasms/drug therapy , Neoplasms/pathology , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Proto-Oncogene Proteins c-akt/metabolism , Pyrimidinones/pharmacology , Pyrimidinones/therapeutic use , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Herein we report investigations into the p38alpha MAP kinase activity of trisubstituted imidazoles that led to the identification of compounds possessing highly potent in vivo activity. The SAR of a novel series of imidazopyridines is demonstrated as well, resulting in compounds possessing cellular potency and enhanced in vivo activity in the rat collagen-induced arthritis model of chronic inflammation.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Imidazoles/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Pyridines/pharmacology , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/metabolism , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Edema/drug therapy , ErbB Receptors/metabolism , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Peptide Fragments/metabolism , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
We report the design and discovery of a 2-aminobenzimidazole-based series of potent and highly selective p38alphainhibitors. The lead compound 1 had low-nanomolar activity in both ATP competitive enzyme binding and inhibition of TNFalpha release in macrophages. Compound 18 showed excellent pharmacokinetics properties and oral activity in the rat collagen induced arthritis model compared with other p38 reference compounds. A SAR strategy to address CyP3A4 liability is also described.
