Discovery of Chiral Dihydropyridopyrimidinones as Potent, Selective and Orally Bioavailable Inhibitors of AKT

Saravanan Parthasarathy, Kenneth Henry, Huaxing Pei, Josh Clayton, Mark Rempala, Deidre Johns, Oscar De Frutos, Pablo Garcia, Carlos Mateos, Sehila Pleite, Yong Wang, Stephanie Stout, Bradley Condon, Sheela Ashok, Zhohai Lu, William Ehlhardt, Tom Raub, Mei Lai, Sandaruwan Geeganage, Timothy P. Burkholder

Index: 10.1016/j.bmcl.2018.03.092

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