Discovery of effective phosphodiesterase 2 inhibitors with antioxidant activities for the treatment of Alzheimer's disease
Discovery of effective phosphodiesterase 2 inhibitors with antioxidant activities for the treatment of Alzheimer's disease
复制标题
发现具有抗氧化活性的有效磷酸二酯酶 2 抑制剂，可用于治疗阿尔茨海默病
DOI：
10.1016/j.bmcl.2021.128016
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发表时间：
2021-04-18
影响因子：
2.7
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Jiang, Mei-Yan;Han, Chuan;Luo, Hai-Bin
由于AD的多因素病理机制，多靶点定向配体（MTDL）策略已广泛应用于治疗阿尔茨海默病（AD）的新药发现。磷酸二酯酶-2 (PDE2) 已被确定为 AD 的一个新颖且有前途的靶点。然而，MTDL 与 PDE2A 和其他抗 AD 因子（如抗氧化剂）的抑制活性相结合尚未开发出来。在此，设计、合成并评估了一系列具有抗氧化能力的新型 PDE2 抑制剂。大多数化合物对 PDE2A 表现出显着的抑制活性以及抗氧化活性。选择化合物6d，其对PDE2A表现出良好的IC50（6.1 nM）、良好的抗氧化活性（ORAC（Trolox）= 8.4当量）并且对SH-SY5Y细胞没有细胞毒性。应用分子对接和动力学模拟来合理设计和解释先导化合物的构效关系（SAR）。
The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer's disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure?activity relationship (SAR) of lead compounds.