Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia.
10.1016/j.apsb.2022.02.012
- Author:
Xu-Nian WU
1
;
Qian ZHOU
1
;
Ya-Dan HUANG
1
;
Xi XIE
2
;
Zhe LI
1
;
Yinuo WU
1
;
Hai-Bin LUO
1
Author Information
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.
- Publication Type:Journal Article
- Keywords:
Binding potencies;
Free energy prediction;
MM-GB/SA;
Phosphodiesterase 8 (PDE8);
Structure-based drug design;
Structure–activity relationship;
Vascular dementia
- From:
Acta Pharmaceutica Sinica B
2022;12(7):3103-3112
- CountryChina
- Language:English
-
Abstract:
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 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 (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.
