非肽类β-分泌酶1(BACE1)抑制剂的研究进展

Advances on non-peptide BACE1 inhibitors

β-分泌酶1(β-site APP cleaving enzyme 1,BACE1)是存在于中枢神经系统的天冬氨酸蛋白酶,能够催化β-淀粉样多肽(Aβ)形成中的第一步也是关键一步的反应,因而被认为是调节认知障碍、治疗阿尔兹海默症(AD)的关键靶点。自2000年BACE1的结构被解析出来后,其抑制剂的研究始终是药物化学领域的热点。随着高通量筛选和基于片段的药物发现等技术的广泛应用,大量非肽类小分子BACE1抑制剂被设计与合成,并且部分化合物已经进入了临床研究阶段。本文对近5年来非肽类BACE1抑制剂的研究进展进行综述。

β-Secretase 1（β-site APP cleaving enzyme 1,BACE1） is a transmembraneaspartyl protease,existing widely in the central nervous system（CNS）.BACE1 is considered to be a key target for adjusting cognitive impairment and treating Alzheimer＇s disease（AD） due to its catalytic function in the first and key step in the production of β-amyloid peptides（A β）.Since the structure of BACE1 was identified in 2000,its inhibitors have always been the research focus in the field of medicinal chemistry.Along with the wide application of modern technology such as high throughput screening（HTS） and fragment-based drug discovery（FBDD）,various non-peptide BACE1 inhibitors with small molecular weights have been designed and developed,even some have been in the clinical trials stage.The research progress on non-peptide BACE1 inhibitors during the recent five years were reviewed in this article.