Mekala Shekar, Nelson Grady, Li Yue-Ming
Chemical Biology Program , Memorial Sloan-Kettering Cancer Center , 1275 York Avenue , New York , New York 10065 , USA . Email:
Pharmacology Graduate Program , Weill Graduate School of Medical Sciences of Cornell University , New York , New York 10021 , USA.
RSC Med Chem. 2020 Aug 27;11(9):1003-1022. doi: 10.1039/d0md00196a. eCollection 2020 Sep 1.
Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disorder, marked by memory loss and a decline in cognitive function. The major hallmarks of AD are the presence of intracellular neurofibrillary tau tangles (NFTs) composed of hyperphosphorylated tau proteins and extracellular plaques composed of amyloid beta peptides (Aβ). The amyloid (Aβ) cascade hypothesis proposes that the AD pathogenesis is initiated by the accumulation of Aβ peptides in the parenchyma of the brain. An aspartyl intramembranal protease called γ-secretase is responsible for the production of Aβ by the cleavage of the amyloid precursor protein (APP). Clinical studies of γ-secretase inhibitors (GSIs) for AD failed due to the lack of substrate specificity. Therefore, γ-secretase modulators (GSMs) have been developed as potential disease modifying agents to modulate the γ-secretase cleavage activity towards the production of toxic Aβ42 peptides. Following the first-generation 'nonsteroidal anti-inflammatory drug' (NSAID) based GSMs, second-generation GSMs (carboxylic acid based NSAID derivatives and non-NSAID derived heterocyclic analogues), as well as natural product-based GSMs, have been developed. In this review, we focus on the recent developments of small molecule-based GSMs that show potential improvements in terms of drug-like properties as well as their current status in human clinical trials and the future perspectives of GSM research.
阿尔茨海默病（AD）是最常见的进行性神经退行性疾病，其特征为记忆力丧失和认知功能下降。AD的主要标志是存在由高度磷酸化的tau蛋白组成的细胞内神经原纤维缠结（NFTs）和由淀粉样β肽（Aβ）组成的细胞外斑块。淀粉样蛋白（Aβ）级联假说提出，AD的发病机制始于Aβ肽在脑实质中的积累。一种名为γ-分泌酶的天冬氨酰膜内蛋白酶负责通过切割淀粉样前体蛋白（APP）产生Aβ。用于AD的γ-分泌酶抑制剂（GSIs）的临床研究因缺乏底物特异性而失败。因此，γ-分泌酶调节剂（GSMs）已被开发为潜在的疾病修饰剂，以调节γ-分泌酶对有毒Aβ42肽产生的切割活性。继第一代基于“非甾体抗炎药”（NSAID）的GSMs之后，第二代GSMs（基于羧酸的NSAID衍生物和非NSAID衍生的杂环类似物）以及基于天然产物的GSMs也已被开发出来。在本综述中，我们重点关注基于小分子的GSMs的最新进展，这些进展在类药性质方面显示出潜在的改善，以及它们在人体临床试验中的现状和GSM研究的未来前景。
