Trends Pharmacol Sci. 2012 May;33(5):233-40. doi: 10.1016/j.tips.2012.02.003. Epub 2012 Apr 4.
Beta-secretase 1 (BACE1) is a central nervous system (CNS) aspartyl protease required for production of amyloid beta (Aβ) peptides. Brain-penetrant BACE1 inhibitors are central to test the 'amyloid hypothesis', which suggests that a reduction of Aβ species in the CNS would halt or even reverse Alzheimer's disease. Discovery of the iminoheterocycle class of BACE1 inhibitors (which show robust efficacy in reduction of CNS Aβ species in animal models) marked an important milestone. These discoveries arose independently from multiple research laboratories that took different paths to end at the same scaffolds. These druggable motifs should be applicable to other aspartyl proteases of therapeutic importance and also to other protein targets involving crucial interactions with carboxylic acid side chains. Here, a comparison of these approaches to BACE1 discovery will showcase how it is important to pay attention to the intrinsic physicochemical properties of the lead series, even at the very early stage of drug discovery.
β-分泌酶 1（BACE1）是一种中枢神经系统（CNS）天冬氨酸蛋白酶，对于淀粉样β（Aβ）肽的产生是必需的。穿透血脑屏障的 BACE1 抑制剂是测试“淀粉样蛋白假说”的关键，该假说表明 CNS 中 Aβ 物种的减少将阻止甚至逆转阿尔茨海默病。含亚氨基杂环的 BACE1 抑制剂的发现（在动物模型中显示出对 CNS Aβ 物种减少的强大功效）标志着一个重要的里程碑。这些发现来自多个研究实验室，它们采用不同的方法最终得到了相同的支架。这些可成药的模体应该适用于其他具有治疗意义的天冬氨酸蛋白酶，以及其他涉及与羧酸侧链关键相互作用的蛋白质靶标。在这里，对这些 BACE1 发现方法的比较将展示即使在药物发现的早期阶段，关注先导系列的固有物理化学性质是多么重要。
