Design, synthesis and evaluation of pyrazolopyrimidinone derivatives as novel PDE9A inhibitors for treatment of Alzheimer?s disease

被引：8
|
作者：
Zhang, Pei [1 ]
Jiang, Mei-Yan [1 ]
Le, Mei-Ling [1 ]
Zhang, Bei [1 ]
Zhou, Qian [1 ]
Wu, Yinuo [1 ]
Zhang, Chen [1 ]
Luo, Hai-Bin [1 ]
机构：
[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 14期
基金：
国家重点研发计划;
关键词：
SYNAPTIC PLASTICITY; PHOSPHODIESTERASE; 9; BAY; 73-6691; IN-VIVO; DISCOVERY; PF-04447943;
D O I：
10.1016/j.bmcl.2020.127254
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer's disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC50 of 2.0 nM against PDE9, showed good metabolic stability (t1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification. © 2020 Elsevier Ltd
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页数：6
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