Laboratorio de Fitoquimica e Quimica Medicinal - LFQM, Instituto de Quimica, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.
Mini Rev Med Chem. 2014 Jan;14(1):2-19. doi: 10.2174/1389557513666131119201353.
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socioeconomic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine- and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi- enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD.
阿尔茨海默病（AD）是一种进行性且无法治愈的神经退行性疾病，对社会经济造成了巨大影响。AD 的进展特点是严重的记忆和认知丧失，导致行为改变、抑郁和死亡。在过去的几十年中，市场上仅推出了几种抗胆碱能药物，主要是乙酰胆碱酯酶抑制剂（AChEIs），用于治疗 AD 的早期和中度阶段。为了寻找新的 AChEIs，以克服对利斯的明和他克林观察到的局限性，杉本及其同事发现了多奈哌齐。除了高活性外，多奈哌齐对 AChE 也具有高选择性和非常低的毒性。在这篇综述中，我们讨论了使多奈哌齐成为 AD 的首选药物的主要结构和药理学特性，以及一个多功能的结构模型，用于设计新型 AChEIs，尽管有多功能和多靶点导向配体。最近许多来自文献的数据表明，全世界都在努力对多奈哌齐的结构进行修改，以期产生具有创新结构模式的新型生物活性化学实体。此外，还通过分子杂交设计了多效配体，得到了利斯的明、他克林和石杉碱甲多奈哌齐的高效选择性 AChEIs。在最近的一项策略中，多奈哌齐的结构特征被用作设计多靶点导向配体的模型，旨在发现新的有效药物候选物，这些候选物可能具有双重或多酶抑制剂的协同药理学活性，作为治疗 AD 的真正创新治疗替代方案。
