Huang Wen-Hai, Sheng Rong, Hu Yong-Zhou
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Curr Med Chem. 2009;16(14):1806-20. doi: 10.2174/092986709788186174.
It is believed that the production and accumulation of beta-amyloid (Abeta) peptide is a critical step to the pathogenesis of Alzheimer's disease (AD). BACE 1 (beta-site APP-cleaving enzyme 1 or beta-secretase), the key enzyme required for generating Abeta from the beta-amyloid precursor protein (APP), is regarded as an ideal target for AD therapeutic drug design. Due to low oral bioavailability, metabolic instability and poor ability to penetrate the central nervous system (CNS) of the existing peptidomimetic inhibitors, researchers have paid more attention to the development of nonpeptidomimetic inhibitors in recent years. A number of drug screening approaches and technologies have been used to identify novel nonpeptidomimetic BACE 1 inhibitors. This review mainly focuses on the recent developments in structure-based design and synthesis of the nonpeptidomimetic BACE 1 inhibitors.
人们认为，β-淀粉样蛋白（Aβ）肽的产生和积累是阿尔茨海默病（AD）发病机制的关键步骤。β-淀粉样前体蛋白裂解酶1（BACE 1，或β-分泌酶）是从β-淀粉样前体蛋白（APP）生成Aβ所需的关键酶，被视为AD治疗药物设计的理想靶点。由于现有的拟肽类抑制剂口服生物利用度低、代谢不稳定且穿透中枢神经系统（CNS）的能力差，近年来研究人员更加关注非肽类抑制剂的开发。许多药物筛选方法和技术已被用于鉴定新型非肽类BACE 1抑制剂。本综述主要关注基于结构的非肽类BACE 1抑制剂设计与合成的最新进展。
