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Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer’s Agents
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-01-18 00:00:00 , DOI: 10.1021/acschemneuro.7b00461
Dawid Panek 1 , Anna Więckowska 1 , Jakub Jończyk 1 , Justyna Godyń 1 , Marek Bajda 1 , Tomasz Wichur 1 , Anna Pasieka 1 , Damijan Knez 2 , Anja Pišlar 2 , Jan Korabecny 3, 4 , Ondrej Soukup 3, 4 , Vendula Sepsova 3, 4 , Raimon Sabaté 5, 6 , Janko Kos 2 , Stanislav Gobec 2 , Barbara Malawska 1
Affiliation  

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer’s disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer’s disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer’s agents.

中文翻译:

1-苄基氨基-2-羟烷基衍生物作为新型潜在疾病修饰多功能抗阿尔茨海默氏病药物的设计,合成和生物学评估

多靶点方法是药物发现中的一种有希望的范例,有可能为复杂的疾病(例如阿尔茨海默氏病)带来新的治疗选择。在本文中,我们提出了一系列独特的1-苄基氨基-2-羟烷基衍生物的发现,这些衍生物结合了对丁酰胆碱酯酶,β-分泌酶,β-淀粉样蛋白和tau蛋白聚集的抑制活性,所有这些都与支持阿尔茨海默氏病的机制有关。值得注意的是,二苯丙胺衍生物10对两种疾病缓解靶标均具有平衡的活性,抑制β-分泌酶(IC 50  h BACE-1 = 41.60μM),抑制淀粉样β聚集(IC 50Aβ)。= 3.09μM),抑制tau聚集(10μM时为55%); 以及针对有症状的靶标,抑制丁酰胆碱酯酶(IC 50  h BuChE = 7.22μM)。它可能代表了开发多功能疾病修饰抗阿尔茨海默氏病药物的令人鼓舞的起点。
更新日期:2018-01-18
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