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Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia
Acta Pharmaceutica Sinica B ; (6): 3103-3112, 2022.
Article in English | WPRIM | ID: wpr-939952
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.

Full text: Available Index: WPRIM (Western Pacific) Type of study: Prognostic study Language: English Journal: Acta Pharmaceutica Sinica B Year: 2022 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Type of study: Prognostic study Language: English Journal: Acta Pharmaceutica Sinica B Year: 2022 Type: Article