血管性痴呆（VaD）是各种脑血管病变所引起的痴呆疾病，患者人数仅次于阿尔茨海默症，尚无理想治疗药物。发现新机制药物已成为VaD研究领域的重大挑战之一。项目组近期发现的黄嘌呤类磷酸二酯酶PDE8高活性抑制剂15，比阳性药多奈哌齐具有更显著的抗VaD药效，且类药性好，提示PDE8抑制剂有望成为全新机制的抗VaD候选药物。但该类抑制剂的PDE亚型选择性还有提升空间。如何提高抑制剂对PDE8的选择性？抑制剂特异性识别PDE8的作用机制又是什么？.在已有基础上，拟定向PDE8的Y748等特异性残基，设计并合成新型黄嘌呤类衍生物；综合其对PDE8抑制效应、PDE各亚型选择性、体内药效和类药性质，发现活性强、选择性高、类药性好的抗VaD先导结构；深入研究先导结构与靶标的相互作用，揭示主导抑制剂选择性的关键性残基，阐明抑制剂特异性识别PDE8的作用机制。本项目为发展抗VaD新策略/新机制药物提供理论依据。

Vascular dementia (VaD) is caused by various cerebrovascular factors, which is the second largest dementia disease after Alzheimer's disease. There is no ideal therapeutic drug at present, so it is of great challenge to discover new mechanism anti-VaD drugs. We constructed a xanthine entity library as PDE8 inhibitors recently discovered that inhibitor 15 exhibits better anti-VaD effect than Donepezil in vivo, suggesting that PDE8 inhibitors may become a new-mechanism anti-VaD drug candidate, but they have the defects of low selectivity. How to improve the selectivity of the PDE8 inhibitors? What is the mechanism of selective inhibitors to identify PDE8? On the basis of recent work, via targeting specific residues such as Y748，we will rationally design and synthesize of novel series of xanthine compounds. After assessing their inhibitory effects on PDE8, PDE subtype selectivity, anti-VaD efficacy, and drug-like properties, we will obtain 1-3 lead structures. In addition，we will perform the interaction study between leads and PDE8, then reveal the impact of key residues on inhibitors’selectivity, and elucidate the molecular mechanism of PDE8-inhibitor recognition. This project will provide theoretical and experimental basis for the development of new strategy/new mechanism anti-VaD drugs.