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.

中文翻译：

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胆碱酯酶和 GSK-3β 双靶点抑制剂调节阿尔茨海默病

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。大多数已批准治疗 AD 的小分子药物旨在解决单一病理特征，例如胆碱能功能障碍或淀粉样蛋白毒性，因此可能无法完全解决该疾病的多因素性质。胆碱酯酶和糖原合成酶激酶 3β (GSK-3β) 的抑制已成为调节 AD 的一种有前途的策略。然而，这两个靶点的双重抑制给分子设计带来了挑战：特别是与靶点参与和生物制药特性相关的问题必须克服。在这篇综述中，我们讨论了胆碱酯酶和 GSK-3β 以及最近报道的双靶点抑制剂的病理生理学作用和结构。我们批判性地评估了胆碱酯酶和 GSK-3β 双靶点抑制剂的发现现状，并强调了进一步的前景。