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 in vitro and in vivo. 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.

中文翻译：

---

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氏病。

我们报告发现一种新型的化合物，其作为中性神经鞘磷脂酶2（nSMase2）和乙酰胆碱酯酶（AChE）的双重抑制剂。这些酶的抑制提供了一种独特的策略来抑制tau病理学在阿尔茨海默氏病（AD）治疗中的传播。我们描述了影响两个相对nSMase2和/或AChE抑制剂的作用和效价的关键SAR元素，此外还鉴定了两个在体外和体内抑制tau基因的外泌体释放的类似物。这些新型的双重nSMase2 / AChE抑制剂的鉴定代表了AD的新治疗方法，并有可能导致开发真正的疾病缓解疗法。