Wu, Xu-Nian; Zhou, Qian; Huang, Ya-Dan; Xie, Xi; Li, Zhe; Wu, Yinuo; Luo, Hai-Bin published the artcile< Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia>, Application of C3H7BrO, the main research area is phosphodiesterase inhibitor vascular dementia mol modeling; Binding potencies; Free energy prediction; MM-GB/SA; Phosphodiesterase 8 (PDE8); Structure-based drug design; Structure–activity relationship; Vascular dementia.
Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chem. 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 2-chloro-9-(3-(2,2-difluoroethoxy)-5-(difluoromethoxy)benzyl)-9H-purin-6-amine 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 2-chloro-9-(3-(2,2-difluoroethoxy)-5-(difluoromethoxy)benzyl)-9H-purin-6-amine 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-2-chloro-9-(3-(2,2-difluoroethoxy)-5-(difluoromethoxy)benzyl)-9H-purin-6-amine complex showed that the potent affinity and high selectivity of 2-chloro-9-(3-(2,2-difluoroethoxy)-5-(difluoromethoxy)benzyl)-9H-purin-6-amine 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.
Acta Pharmaceutica Sinica B published new progress about Brain. 6482-24-2 belongs to class ethers-buliding-blocks, and the molecular formula is C3H7BrO, Application of C3H7BrO.
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem