Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders. Herein, based on the existing PDE2 inhibitors and their binding modes, a series of purin-6-one derivatives were designed, synthesized and evaluated for PDE2 inhibitory activities, which led to the discovery of the best compounds 6p and 6s with significant inhibitory potency (IC50: 72 and 81 nM, respectively). Docking simulation was performed to insert compound 6s into the crystal structure of PDE2 at the active site to determine the binding mode. Furthermore, compound 6s significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cAMP and cGMP levels. It also produced anxiolytic-like effect in the elevated plus-maze test and exhibited favorable pharmacokinetic properties in vivo. These results might bring significant instruction for further development of potent PDE2 inhibitors.

中文翻译：

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设计，合成作为磷酸二酯酶2（PDE2）抑制剂的新型嘌呤6-1衍生物：具有神经保护作用和抗焦虑作用。

磷酸二酯酶2（PDE2）在中枢神经系统（CNS）疾病的潜在治疗方面受到了广泛关注。在此，根据现有的PDE2抑制剂及其结合模式，设计，合成了一系列嘌呤6-1衍生物并评估了其对PDE2的抑制活性，从而发现了具有明显抑制潜能的最佳化合物6p和6s（ IC50：分别为72和81 nM。进行对接模拟以将化合物6s插入到活性位点的PDE2的晶体结构中，以确定结合模式。此外，化合物6s显着保护了HT-22细胞免受皮质酮诱导的细胞毒性，并挽救了皮质酮诱导的cAMP和cGMP水平下降。它还在高迷宫试验中产生了类似抗焦虑的作用，并在体内表现出有利的药代动力学特性。这些结果可能为进一步开发有效的PDE2抑制剂提供重要指导。