1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-¦Â aggregation crossing the blood-brain barrier

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• 作者：Michaela Prinz ; S¨¹l¨¹nay Parlar ; G¨¹l?ah Bayraktar ; Vildan Alpt¨¹z¨¹n ; Ercin Erciyas ; Adyary Fallarero ; Daniela Karlsson ; Pia Vuorela ; Malgorzata Burek ; Carola F?rster ; Ezgi Turunc ; Guliz Armagan ; Ayfer Yalcin ; Carola Schiller ; Kristina Leuner ; Manuel Krug ; Christoph A. Sotriffer ; Ulrike Holzgrabe
• 关键词：AChEIs ; acetylcholinesterase inhibitors ; AD ; Alzheimer&rsquo ; s disease ; APOE ; apolipoprotein ; APP ; amyloid precursor protein ; BuChEI ; butyrylcholinesterase inhibitor ; cEND ; cerebral capillary endothelial ; COX ; cyclooxygenase ; DCF ; dichlorofluorescein ; DCF
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2013
• 出版时间：16 July, 2013
• 年：2013
• 卷：49
• 期：4
• 页码：603-613
• 全文大小：657 K

文摘

Given the fundamentally multifactorial character of Alzheimer¡¯s disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid ¦Â fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC₅₀ = 90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.