Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase

doi:10.1016/j.bmc.2008.12.067

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第二研究室

	Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase
	Zhu, Yiping 1; Xiao, Kun 1; Ma, Lanping1 ; Xiong, Bin 1; Fu, Yan 1; Yu, Haiping 2; Wang, Wei 1; Wang, Xin1 ; Hu, Dingyu 1; Peng, Hongli1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2009-02-15
卷号	17 期号:4 页码:1600-1613
关键词	AD AChE BACE-1 Dual inhibitor HE HMC HEA
ISSN号	0968-0896
DOI	10.1016/j.bmc.2008.12.067
文献子类	Article
英文摘要	To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC50 = 0.567 mu M; AChE: IC50 = 1.83 mu M), and also showed excellent inhibitory effects on Ab production of APP transfected HEK293 cells (IC50 = 98.7 nM) and mild protective effect against hydrogen peroxide (H2O2)-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of A beta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients. (c) 2009 Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[30230400] ; National Natural Science Foundation of China[30672538] ; National Natural Science Foundation of China[30572169] ; Ministry of Science and Technology of China[2004CB518907] ; '863' Hi-Tech Program of China[2004 AA2 Z3781] ; State Key Program of Basic Research of China[2004GB518907]
WOS关键词	COMBAT ALZHEIMERS-DISEASE ; TARGET-DIRECTED LIGANDS ; X-RAY-STRUCTURE ; POTENT INHIBITORS ; POLYAMINE BACKBONE ; BACE1 INHIBITORS ; ANTIACETYLCHOLINESTERASE ACTIVITY ; PEPTIDOMIMETIC INHIBITORS ; COUMARIN DERIVATIVES ; AMYLOID AGGREGATION
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000263502300022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279311]
专题	药理学第二研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室国家新药筛选中心
通讯作者	Zhang, Haiyan
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Yiping,Xiao, Kun,Ma, Lanping,et al. Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2009,17(4):1600-1613.
APA	Zhu, Yiping.,Xiao, Kun.,Ma, Lanping.,Xiong, Bin.,Fu, Yan.,...&Shen, Jingkang.(2009).Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase.BIOORGANIC & MEDICINAL CHEMISTRY,17(4),1600-1613.
MLA	Zhu, Yiping,et al."Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase".BIOORGANIC & MEDICINAL CHEMISTRY 17.4(2009):1600-1613.