丁酰胆碱酯酶在阿尔茨海默病中的作用及其抑制剂设计策略

近年来，随着预期寿命的增长，全球人口老龄化逐渐加剧，多种老年疾病为社会保障体系以及个人家庭生活带来诸多压力，其中最为常见的一种便是阿尔茨海默病。目前临床试验中用于治疗阿尔茨海默病的药物绝大部分都是基于胆碱能假说，该类药物通过抑制乙酰胆碱酯酶来提高患者脑内乙酰胆碱水平，从而改善认知功能。但其普遍存在着对于中后期患者疗效不佳以及副作用较大等问题。在中后期阿尔茨海默病患者脑中，乙酰胆碱酯酶水平异常下降，而同样具有水解乙酰胆碱功能的丁酰胆碱酯酶水平代偿性上升，因此，此时抑制丁酰胆碱酯酶成为了更好的选择。此外，丁酰胆碱酯酶作为靶标具有良好的安全性，选择性抑制丁酰胆碱酯酶不会引起乙酰胆碱酯酶抑制剂类似的外周副作用。综述了丁酰胆碱酯酶在阿尔茨海默病中的作用及其抑制剂设计策略的研究进展。

The Role of Butyrylcholinesterase in Alzheimer's Disease and Design Strategies of Its Inhibitors

In recent years, with the increase of life expectancy, the global population is aging. A variety of geriatric diseases have put a lot of pressure on the social security system and individual family life, and one of the most common geriatric diseases is Alzheimer's disease. Most of the experimental drugs currently in the clinical development for the treatment of AD are based on the cholinergic hypothesis. By inhibiting acetylcholinesterase (AChE), these medications raise the level of acetylcholine (ACh) in the brain of patients to improve cognitive function. However, this kind of drugs generally have some problems, such as poor efficacy in patients with the mid- to late-stage AD, and significant side effects. In the brains of the patients with the mid- and late-stage AD, AChE levels declines abnormally, whereas the level of butyrylcholinesterase (BChE), which also hydrolyzes ACh, rises compensatingly. Therefore, inhibition of BChE becomes a better choice at this time. Additionally, BChE has a good safety profile as a target, and selective inhibition of BChE doesn't cause the peripheral side effects similar to those of AChE inhibitors. This article has reviewed the advances in research on the role of BChE in Alzheimer's disease and the design strategies of BChE inhibitors.