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

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• 作者：Yiping Zhu ; Kun Xiao ; Lanping Ma ; Bin Xiong ; Yan Fu ; Haiping Yu ; Wei Wang ; Xin Wang ; Dingyu Hu ; Hongli Peng ; Jingya Li ; Qi Gong ; Qian Chai ; Xican Tang ; Haiyan Zhang ; Jia Li ; Jingkang Shen
• 关键词：AD ; AChE ; BACE-1 ; Dual inhibitor ; HE ; HMC ; HEA
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：15 February 2009
• 年：2009
• 卷：17
• 期：4
• 页码：1600-1613
• 全文大小：1697 K

文摘

To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-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 μM; AChE: IC₅₀ = 1.83 μM), and also showed excellent inhibitory effects on Aβ 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 Aβ_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.