Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severny proezd 1, Chernogolovka, Moscow region, 142432, Russia.
Med Res Rev. 2017 Sep;37(5):1186-1225. doi: 10.1002/med.21434. Epub 2017 Jan 13.
Alzheimer's disease (AD) is characterized by a chronic and progressive neurodegenerative process resulting from the intracellular and extracellular accumulation of fibrillary proteins: beta-amyloid and hyperphosphorylated Tau. Overaccumulation of these aggregates leads to synaptic dysfunction and subsequent neuronal loss. The precise molecular mechanisms of AD are still not fully understood but it is clear that AD is a multifactorial disorder and that advanced age is the main risk factor. Over the last decade, more than 50 drug candidates have successfully passed phase II clinical trials, but none has passed phase III. Here, we summarize data on current "anti-Alzheimer's" agents currently in clinical trials based on findings available in the Thomson Reuters «Integrity» database, on the public website www.clinicaltrials.gov, and on database of the website Alzforum.org. As a result, it was possible to outline some major trends in AD drug discovery: (i) the development of compounds acting on the main stages of the pathogenesis of the disease (the so-called "disease-modifying agents") - these drugs could potentially slow the development of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal; (ii) focused design of multitargeted drugs acting on multiple molecular targets involved in the pathogenesis of the disease; (3) finally, the repositioning of old drugs for new (anti-Alzheimer's) application offers a very attractive approach to facilitate the completion of clinical trials.
阿尔茨海默病（AD）的特征是一种慢性和进行性神经退行性过程，是由纤维状蛋白质：β-淀粉样蛋白和过度磷酸化的 Tau 在细胞内和细胞外的积累引起的。这些聚集物的过度积累导致突触功能障碍和随后的神经元丢失。AD 的精确分子机制尚不完全清楚，但很明显 AD 是一种多因素疾病，年龄增长是主要的危险因素。在过去的十年中，有 50 多种候选药物成功地通过了 II 期临床试验，但没有一种药物通过了 III 期临床试验。在这里，我们根据 Thomson Reuters 的“Integrity”数据库、公共网站 www.clinicaltrials.gov 以及 Alzforum.org 网站上的数据库中提供的发现，总结了目前处于临床试验阶段的“抗阿尔茨海默病”药物的数据。结果，有可能概述 AD 药物发现的一些主要趋势：（i）开发作用于疾病发病机制主要阶段的化合物（所谓的“疾病修饰剂”）-这些药物有可能减缓中枢神经系统结构和功能异常的发展，提供持续的认知功能改善，即使在停药后也能持续改善；（ii）针对参与疾病发病机制的多个分子靶点的多靶点药物的有针对性设计；（3）最后，将旧药物重新用于新的（抗阿尔茨海默病）用途是一种非常有吸引力的方法，有助于完成临床试验。
