双重中性鞘磷脂酶 2/乙酰胆碱酯酶抑制剂治疗阿尔茨海默病。
Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
机构信息
Drug Discovery Laboratory, Department of Neurology, Mary S. Easton Center for Alzheimer's Disease Research, University of California, Los Angeles, California 90095, United States.
School of Nursing, University of California, Los Angeles, California 90095, United States.
出版信息
ACS Chem Biol. 2020 Jun 19;15(6):1671-1684. doi: 10.1021/acschembio.0c00311. Epub 2020 May 14.
Abstract
We report the discovery of a novel class of compounds that function as dual inhibitors of the enzymes neutral sphingomyelinase-2 (nSMase2) and acetylcholinesterase (AChE). Inhibition of these enzymes provides a unique strategy to suppress the propagation of tau pathology in the treatment of Alzheimer's disease (AD). We describe the key SAR elements that affect relative nSMase2 and/or AChE inhibitor effects and potency, in addition to the identification of two analogs that suppress the release of tau-bearing exosomes and . Identification of these novel dual nSMase2/AChE inhibitors represents a new therapeutic approach to AD and has the potential to lead to the development of truly disease-modifying therapeutics.
摘要
我们报告了一类新型化合物的发现，它们可以作为神经鞘氨醇酶-2（nSMase2）和乙酰胆碱酯酶（AChE）的双重抑制剂。抑制这些酶为抑制阿尔茨海默病（AD）中 tau 病理的传播提供了一种独特的策略。我们描述了影响相对 nSMase2 和/或 AChE 抑制作用和效力的关键 SAR 元素，此外还鉴定了两种类似物，它们可以抑制携带 tau 的外泌体的释放。鉴定这些新型双重 nSMase2/AChE 抑制剂代表了一种治疗 AD 的新方法，并有潜力开发真正的疾病修饰疗法。
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