School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
Eur J Med Chem. 2022 Nov 15;242:114695. doi: 10.1016/j.ejmech.2022.114695. Epub 2022 Aug 27.
Due to the hugely important roles of neurotransmitter acetylcholine (ACh) and amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), the development of multi-target directed ligands (MTDLs) focused on cholinesterase (ChE) and Aβ becomes one of the most attractive strategies for combating AD. To date, numerous preclinical studies toward multifunctional conjugates bearing ChE inhibition and anti-Aβ aggregation have been reported. Noteworthily, most of the reported multifunctional cholinesterase inhibitors are carbamate-based compounds due to the initial properties of carbamate moiety. However, because their easy hydrolysis in vivo and the instability of the compound-enzyme conjugate, the mechanism of action of these compounds is rare. Thus, non-carbamate compounds are of great need for developing novel cholinesterase inhibitors. Besides, given that Aβ accumulation begins to occur 10-15 years before AD onset, modulating Aβ is ineffective only in inhibiting its aggregation but not eliminate the already accumulated Aβ if treatment is started when the patient has been diagnosed as AD. Considering the limitation of current Aβ accumulation modulators in ameliorating cognitive deficits and ineffectiveness of ChE inhibitors in blocking disease progression, the development of a practically valuable strategy with multiple pharmaceutical properties including ChE inhibition and Aβ modulation for treating AD is indispensable. In this review, we focus on summarizing the scaffold characteristics of reported non-carbamate cholinesterase inhibitors with Aβ modulation since 2020, and understanding the ingenious multifunctional drug design ideas to accelerate the pace of obtaining more efficient anti-AD drugs in the future.
由于神经递质乙酰胆碱（ACh）和淀粉样β（Aβ）在阿尔茨海默病（AD）发病机制中的重要作用，针对胆碱酯酶（ChE）和 Aβ 的多靶标定向配体（MTDLs）的开发成为对抗 AD 的最有吸引力的策略之一。迄今为止，已经报道了许多针对具有 ChE 抑制和抗 Aβ聚集作用的多功能缀合物的临床前研究。值得注意的是，由于氨基甲酸酯部分的初始性质，大多数报道的多功能胆碱酯酶抑制剂都是氨基甲酸酯类化合物。然而，由于它们在体内易于水解以及化合物-酶缀合物的不稳定性，这些化合物的作用机制很少。因此，需要开发新型胆碱酯酶抑制剂。此外，由于 Aβ 的积累在 AD 发病前 10-15 年就开始发生，因此如果在患者被诊断为 AD 时开始治疗，调节 Aβ 仅能抑制其聚集，而不能消除已经积累的 Aβ，从而导致 Aβ 聚集调节剂的作用有限。考虑到目前 Aβ 积累调节剂在改善认知缺陷方面的局限性以及 ChE 抑制剂在阻止疾病进展方面的无效性，开发一种具有多种药物特性的实用价值策略，包括 ChE 抑制和 Aβ 调节，对于治疗 AD 是必不可少的。在这篇综述中，我们重点总结了 2020 年以来报道的具有 Aβ 调节作用的非氨基甲酸酯类胆碱酯酶抑制剂的骨架特征，并深入了解了巧妙的多功能药物设计思路，以加速未来获得更有效抗 AD 药物的步伐。
