Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.,ACS Chemical Biology

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Dual Neutral Sphingomyelinase-2/Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-04-30 , DOI: 10.1021/acschembio.0c00311
Tina Bilousova _{1,

2} , Bryan J Simmons ₃ , Rachel R Knapp ₃ , Chris J Elias ₁ , Jesus Campagna ₁ , Mikhail Melnik ₂ , Sujyoti Chandra ₁ , Samantha Focht ₁ , Chunni Zhu ₁ , Kanagasabai Vadivel ₁ , Barbara Jagodzinska ₁ , Whitaker Cohn ₁ , Patricia Spilman ₁ , Karen H Gylys ₂ , Neil K Garg ₃ , Varghese John ₁

Affiliation

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：

用于治疗阿尔茨海默病的双中性鞘磷脂酶 2/乙酰胆碱酯酶抑制剂。

我们报告发现了一类新型化合物，它们可作为中性鞘磷脂酶-2 (nSMase2) 和乙酰胆碱酯酶 (AChE) 酶的双重抑制剂。在阿尔茨海默病 (AD) 的治疗中，抑制这些酶提供了一种抑制 tau 病理学传播的独特策略。我们描述了影响 nSMase2 和/或 AChE 抑制剂相对作用和效力的关键 SAR 元件，以及在体外和体内抑制 tau 蛋白外泌体释放的两种类似物的鉴定。这些新型 nSMase2/AChE 双重抑制剂的鉴定代表了 AD 的一种新治疗方法，并有可能导致真正改善疾病的疗法的开发。

更新日期：2020-06-19

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