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...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.展开更多
基金supported by the Natural Science Foundation of China(21877134,22077143,81903542,and 21977127)Science Foundation of Guangzhou City(201904020023,China)+3 种基金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)。
文摘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.
