Developing β-secretase inhibitors for treatment of Alzheimer's disease.
Developing β-secretase inhibitors for treatment of Alzheimer's disease.
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DOI：
10.1111/j.1471-4159.2011.07476.x
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发表时间：
2012-01
影响因子：
4.7
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Ghosh AK;Brindisi M;Tang J
β-分泌酶（memapsin 2; BACE1）是脑内淀粉样蛋白前体蛋白加工过程中的第一个蛋白酶，导致淀粉样蛋白-β (Aβ)的产生。人们认为，高水平的脑Aβ与阿尔茨海默病（AD）的发病有关。因此，β分泌酶是开发抑制剂药物的主要治疗靶点。在过去的十年中，β-分泌酶抑制剂朝着更好的药物性能发展取得了稳步的进展。最近的抑制剂是有效的，选择性的，并已被证明可以穿透血脑屏障，抑制实验动物大脑中的Aβ水平。此外，持续给药β分泌酶抑制剂被证明可以挽救转基因AD小鼠与年龄相关的认知衰退。少数β分泌酶抑制剂也已进入早期临床试验。这些进展为阿尔茨海默病治疗药物的临床开发提供了一些乐观。
β-Secretase (memapsin 2; BACE1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-β (Aβ) in the brain. It is believed that high levels of brain Aβ are responsible for the pathogenisis of Alzheimer’s disease (AD). Therefore, β-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of β-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit Aβ level in the brains of experimental animals. Moreover, continuous administration of a β-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of β-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.
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