基于分子片段药物发现技术的β-分泌酶抑制剂研究进展

Fragment-based drug discovery:recent developments in β-secretase inhibitors

β-分泌酶抑制剂是开发新型阿尔茨海默病治疗药物的重要研究方向,基于分子片段的药物发现技术是近年来发展的一种基于靶标的药物研究策略。本文综述了近年来利用这一技术发现β-分泌酶抑制剂的研究进展。

β-secretase（ also called BACE1 ） is an attractive druggable target for discovering novel AD drug. In the past decade, thousands of BACE1 inhibitors of transition state analogues have been discovered since the structure of BACE1 was resolved. Although some compounds are potent activity and selectivity against BACE1, the poor brain-penetrativity and ADME of these BACE1 inhibitors restrict to develop them into a clinical drug for AD. The field of fragment-based drug discovery （FBDD） has developed significantly over the past 10 years and is now recognized as a tangible alternative to more traditional methods of hit identification. This method can improve the efficiency of lead discovery, the lead-likeness of hit and chemical space of structural optimization of lead compounds. Some excellent BACE1 inhibitors with potent activity and selectivity and brain-penetrativity have been discovered by FBDD since this method was first used to design BACE1 inhibitors in 2006. This review will focus on the recent developments in discovery of BACE1 inhibi tors based FBDD method.