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
A series of domino reactions in which the intramolecular Schmidt reaction is combined with either a Sakurai reaction, an aldol reaction, or both is reported. The Sakurai reaction of an allylsilane with an azido-containing enone under Lewis acidic conditions followed by protonation of the resulting titanium enolate species allowed for a subsequent intramolecular Schmidt reaction. Alternatively, the intermediate titanium enolate could undergo an aldol reaction followed by the intramolecular Schmidt reaction to form lactam products with multiple stereogenic centers. The stereochemical features of the titanium enolate aldol reaction with several 3-azidoaldehyde substrates during this domino process is discussed.
