从乙酰胆碱酯酶抑制剂到β-分泌酶1抑制剂：茚满酮骨架上胺基的作用。
From AChE to BACE1 inhibitors: The role of the amine on the indanone scaffold.
作者信息
Rampa Angela, Mancini Francesca, De Simone Angela, Falchi Federico, Belluti Federica, Di Martino Rita Maria Concetta, Gobbi Silvia, Andrisano Vincenza, Tarozzi Andrea, Bartolini Manuela, Cavalli Andrea, Bisi Alessandra
机构信息
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
出版信息
Bioorg Med Chem Lett. 2015 Jul 15;25(14):2804-8. doi: 10.1016/j.bmcl.2015.05.002. Epub 2015 May 9.
In recent years, a progressive increase in age-related disorders could be observed in most western countries, among which Alzheimer's disease (AD) is one of the most challenging. BACE1 could be seen as an attractive target to develop disease-modifying compounds, and in this context, a new series of hybrid molecules was designed and synthesized, based on a previously identified multitarget lead compound. In particular, the amino side chain was appropriately modified to fit BACE1 as additional target. In vitro testing results pointed out compound 8 (IC50=2.49±0.08 μM), bearing the bulky bis(4-fluorophenyl)methyl)piperazine substituent, as the most potent BACE1 inhibitor of the series.
近年来，在大多数西方国家，可以观察到与年龄相关的疾病呈逐渐上升趋势，其中阿尔茨海默病（AD）是最具挑战性的疾病之一。β-分泌酶1（BACE1）可被视为开发疾病修饰化合物的一个有吸引力的靶点，在此背景下，基于先前鉴定的多靶点先导化合物，设计并合成了一系列新的杂化分子。特别是，对氨基侧链进行了适当修饰，使其适合作为额外靶点的BACE1。体外测试结果表明，带有庞大的双（4-氟苯基）甲基）哌嗪取代基的化合物8（IC50=2.49±0.08μM）是该系列中最有效的BACE1抑制剂。
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