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.
View MoreContact:86-791-86629460
Address:1-6F, 118 Xinzhou road, Nanchang, Jiangxi, China
Wuhan Fortuna Chemical Co.,Ltd
website:http://www.fortunachem.com
Contact:86-27-59207850
Address:Add: Room 2015, No.2 Building, Kaixin Mansion No.107 Jinqiao Avenue, Wuhan, China
Yurui(Shanghai)Chemical Co.,Ltd
Contact:0086 21-50456736
Address:No.3188 Xiupu Road,Shanghai
RongCheng Tianyu Technology Co.,Ltd.
Contact:86-631-7519595
Address:220Ping Donghai Road RongChengCity,ShangDong Province China
QINGDAO DEVELOP chemistry Co.,Limited
Contact:+86-532-85807910
Address:98#Nanjing Road, Qingdao, China 266071
Doi:10.1007/BF00598215
(1988)Doi:10.1002/chem.200903353
(2010)Doi:10.1002/anie.201601834
(2016)Doi:10.1002/jhet.307
(2010)Doi:10.1021/co400162m
(2014)Doi:10.1021/acs.inorgchem.0c00638
(2020)