Ghosh Arun K, Bilcer Geoffrey, Hong Lin, Koelsch Gerald, Tang Jordan
Department of Chemistry and Medical Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Curr Alzheimer Res. 2007 Sep;4(4):418-22. doi: 10.2174/156720507781788864.
A major strategy for the development of a disease-modifying therapy against Alzheimer's disease is pharmacological intervention designed to reduce levels of beta-amyloid in the brain. Among various ways of reducing beta-amyloid production, the inhibition of beta-secretase (memapsin 2, BACE) is particularly attractive. Not only does beta-secretase initiates the amyloid cascade, it also is an aspartic protease, a class of proteases for which successful inhibitor drugs have been developed to treat AIDS patients. Extensive efforts in research and development of a beta-secretase inhibitor drug have taken place in many laboratories during the past few years. However, no drug candidate is currently in clinical trials. In spite of the lack of obvious success, much progress has been made to incorporate the drug-like properties in the evolution of better inhibitors. The inhibitors from more recent generations are indeed similar in characteristics to other protease inhibitor drugs. This progress permits optimism that development of clinical candidates of beta-secretase inhibitor drugs is a realistic goal.
开发针对阿尔茨海默病的疾病修饰疗法的一项主要策略是进行药物干预，旨在降低大脑中β-淀粉样蛋白的水平。在降低β-淀粉样蛋白产生的各种方法中，抑制β-分泌酶（膜天冬氨酸蛋白酶2，BACE）尤其具有吸引力。β-分泌酶不仅启动了淀粉样蛋白级联反应，它还是一种天冬氨酸蛋白酶，针对这类蛋白酶已经开发出了成功的抑制剂药物用于治疗艾滋病患者。在过去几年里，许多实验室都在广泛开展β-分泌酶抑制剂药物的研发工作。然而，目前尚无候选药物进入临床试验。尽管缺乏明显的成功，但在更好的抑制剂的研发过程中，在融入类药特性方面已经取得了很大进展。最新一代的抑制剂在特性上确实与其他蛋白酶抑制剂药物相似。这一进展让人乐观地认为，开发β-分泌酶抑制剂药物的临床候选药物是一个现实的目标。
