Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors

被引：35
作者：
Liu, Jian [1 ]
Chen, Wuyan [2 ]
Xu, Yechun [2 ]
Ren, Sumei [1 ]
Zhang, Wei [1 ]
Li, Yingxia [1 ]
机构：
[1] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
[2] Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 09期
基金：
国家高技术研究发展计划(863计划); 中国国家自然科学基金;
关键词：
Alzheimer's disease; beta-Secretase; BACE1; inhibitor; Synthesis; Docking; AMYLOID PRECURSOR PROTEIN; HUMAN BETA-SECRETASE; CONFORMATIONAL RESTRICTION APPROACH; HUMAN BRAIN; PEPTIDOMIMETIC INHIBITORS; ASPARTIC PROTEASES; ALZHEIMERS-DISEASE; POTENT INHIBITORS; DRUG DISCOVERY; IDENTIFICATION;
D O I：
10.1016/j.bmc.2015.03.034
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Nineteen new derivatives based on the structure of marine natural product tasiamide B were designed, synthesized, and evaluated for their inhibitory activity against BACE1, a potential therapeutic target for Alzheimer's disease. The hydrophobic substituents Val at P-3 position, Leu at P-1' position, Ala at P-2' position, and Phe at P-3' position were found to significantly affect the inhibition. Free carboxylic acid at C-terminus was also found to be important to the activity. In addition, the structure-activity relationships (SARs) were supported by molecular docking simulation. (C) 2015 Published by Elsevier Ltd.
引用
收藏
页码：1963 / 1974
页数：12
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