Abstract：
Alzheimer\'s disease (AD) is a neurodegenerative disease that affects over 55 million patients worldwide. Most of the approved small-molecule drugs for AD have been designed to tackle a single pathological hallmark, such as cholinergic dysfunction or amyloid toxicity, and thus may not fully address the multifactorial nature of the disease. Inhibition of both cholinesterase and glycogen synthase kinase-3β (GSK-3β) has emerged as a promising strategy to modulate AD. However, the dual inhibition of these two targets posts challenges in molecular design: issues related to target engagements and biopharmaceutical properties in particular must be overcome. In this review, we discuss the physiopathological roles and structures of cholinesterase and GSK-3β as well as recently reported dual-target inhibitors. We critically evaluate the current status of the discovery of dual-target inhibitors of cholinesterase and GSK-3β, and highlight further perspectives.
摘要：
阿尔茨海默病（AD）是一种神经退行性疾病，影响全球超过5500万患者。大多数批准的AD小分子药物都是为了解决单一的病理标志，如胆碱能功能障碍或淀粉样蛋白毒性，因此可能不能完全解决疾病的多因素性质。胆碱酯酶和糖原合酶激酶-3β（GSK-3β）的抑制已成为调节AD的有希望的策略。然而,这两个靶点的双重抑制给分子设计带来了挑战:必须克服与靶点参与和生物制药特性相关的问题。在这次审查中,我们讨论了胆碱酯酶和GSK-3β的生理病理作用和结构以及最近报道的双靶点抑制剂。我们严格评估胆碱酯酶和GSK-3β双靶点抑制剂的发现现状，并强调进一步的观点。
