Bioorganic and Medicinal Chemistry Letters p. 1887 - 1891 (2018)
Update date:2022-07-30
Topics:
Parthasarathy, Saravanan
Henry, Kenneth
Pei, Huaxing
Clayton, Josh
Rempala, Mark
Johns, Deidre
De Frutos, Oscar
Garcia, Pablo
Mateos, Carlos
Pleite, Sehila
Wang, Yong
Stout, Stephanie
Condon, Bradley
Ashok, Sheela
Lu, Zhohai
Ehlhardt, William
Raub, Tom
Lai, Mei
Geeganage, Sandaruwan
Burkholder, Timothy P.
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.
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