1177447-31-2

Upstream product

• 1092460-40-6 methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate 
• 1295516-49-2 methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate 

Relevant academic research and scientific papers

AKT INHIBITOR

The present invention discloses an AKT inhibitor, and specifically relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof. The present invention further provides a preparation method thereof, and the use thereof in prevention and/or treatment of a disease mediated by AKT protein kinase.

Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT

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 GSK3β in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.

AKT INHIBITORS

The present invention provides AKT inhibitors of the formula: Formula I The present invention also provides pharmaceutical compositions comprising compounds of Formula I, uses of compounds of Formula I and method of using compounds of Formula I.