摘要Our previous study demonstrated that phosphodiesterase 8(PDE8)could work as a potential target for vascular dementia(VaD)using a chemical probe 3a.However,compound 3a is a chiral com-pound 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 ex-hibited potent inhibitory activity against PDE8A(IC50=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 cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD 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-shaped π—π interactions 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.