Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
Bioorg Med Chem. 2011 Jan 1;19(1):145-55. doi: 10.1016/j.bmc.2010.11.042. Epub 2010 Nov 26.
Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.
在过去十年中，BACE-1 蛋白酶抑制剂已成为治疗阿尔茨海默病的一种很有前途的药物策略。在本报告中，基于 α-苯丁氨酯、α-苄基丁氨酯、异丝氨酸和 β-丙氨酸部分，已制备了超过 20 种新型 BACE-1 蛋白酶抑制剂。抑制剂通过应用 Fmoc 固相法合成，并对其抑制性质进行了评价。最有效的抑制剂，含叔醇的 (R)-12（IC50=0.19μM）与 BACE-1 蛋白酶的活性部位共结晶，提供了一种新的结合模式，其中 N 端胺与一个催化天冬氨酸形成氢键。
