Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia  

作　　者：Xu-Nian Wu Qian Zhou Ya-Dan Huang Xi Xie Zhe Li Yinuo Wu Hai-Bin Luo 

机构地区：[1]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,510006,China [2]Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute,School of Pharmaceutical Sciences,Hainan University,Haikou 570228,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第7期3103-3112,共10页药学学报（英文版）

基　　金：supported by the Natural Science Foundation of China(21877134,22077143,81903542,and 21977127);Science Foundation of Guangzhou City(201904020023,China);Fundamental Research Funds for Hainan University(KYQD(ZR)21031,China);Science Foundation of Guangdong Province(2019A1515011883,China);Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China);Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China)。

摘　　要：Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(Va D)using a chemical probe 3a.However,compound 3a is a chiral compound which was obtained by chiral resolution on HPLC,restricting its usage in clinic.Herein,a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors.Lead 15 exhibited potent inhibitory activity against PDE8A(IC_(50)=11 nmol/L),high selectivity over other PDEs,and remarkable drug-like properties(worthy to mention is that its bioavailability was up to 100%).Oral administration of 15 significantly improved the c AMP level of the right brain and exhibited dosedependent effects on cognitive improvement in a Va D mouse model.Notably,the X-ray crystal structure of the PDE8A—15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shapedπ—πinteractions with Phe785 as well as a unique H-bond network,which have never been observed in other PDE-inhibitor complex before,providing new strategies for the further rational design of novel selective inhibitors against PDE8.

关 键 词：Phosphodiesterase 8(PDE8) Vascular dementia Structure-based drug design MM-GB/SA Free energy prediction Structure—activity relationship Binding potencies 

分 类 号：R914[医药卫生—药物化学]