Discovery of Potent, Selective, and Direct Acid Sphingomyelinase Inhibitors with Antidepressant Activity.,Journal of Medicinal Chemistry

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Discovery of Potent, Selective, and Direct Acid Sphingomyelinase Inhibitors with Antidepressant Activity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-28 , DOI: 10.1021/acs.jmedchem.9b00739
Kan Yang _{1,

2} , Jinying Yu ₁ , Keyi Nong ₁ , Youzhi Wang ₁ , Ao Niu ₁ , Wenlu Chen ₁ , Jibin Dong ₃ , Jinxin Wang ₁

Affiliation

Recent studies on sphingolipids suggest that acid sphingomyelinase (ASM), which plays a central role in the pathogenesis of major depression, is emerging to be a novel target for developing antidepressants. Herein we first described the design, synthesis, and biological evaluation of hydroxamic acid-based direct inhibitors of ASM with the effort of validating their antidepressant effects in vivo. As a result, a series of novel ASM inhibitors were developed using a structure-based approach. Our studies demonstrated that the administration of 21b improved depression-like behaviors of rats. Importantly, this positive result was relevant to the inhibition of ASM and the increasing neurogenesis in hippocampus. To the best of our knowledge, this is the first time that direct inhibitors of ASM were developed to support the possibility of ASM as a potential therapeutic target for depression.

中文翻译：

发现具有抗抑郁活性的有效，选择性和直接酸性鞘氨醇酶抑制剂。

最近对鞘脂的研究表明，在主要抑郁症的发病机理中起着重要作用的酸性鞘磷脂酶（ASM）逐渐成为开发抗抑郁药的新靶标。在本文中，我们首先描述了基于异羟肟酸的ASM直接抑制剂的设计，合成和生物学评估，以验证它们在体内的抗抑郁作用。结果，使用基于结构的方法开发了一系列新颖的ASM抑制剂。我们的研究表明，施用21b可以改善大鼠的抑郁样行为。重要的是，该阳性结果与抑制ASM和增加海马神经发生有关。据我们所知，

更新日期：2020-01-29

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