Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy , China Pharmaceutical University , Nanjing 210009 , China.
Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmaceutical Sciences , Hebei University , Baoding 071002 , China.
J Med Chem. 2020 Feb 13;63(3):961-974. doi: 10.1021/acs.jmedchem.9b00739. Epub 2020 Jan 28.
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 . As a result, a series of novel ASM inhibitors were developed using a structure-based approach. Our studies demonstrated that the administration of 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.
最近的鞘脂研究表明，在重度抑郁症发病机制中起核心作用的酸性鞘磷脂酶（ASM），正逐渐成为开发抗抑郁药的新靶点。在此，我们首次描述了基于羟肟酸的 ASM 直接抑制剂的设计、合成和生物学评价，努力验证其抗抑郁作用。结果，我们采用基于结构的方法开发了一系列新型 ASM 抑制剂。研究表明，可改善大鼠的抑郁样行为。重要的是，这一积极结果与 ASM 的抑制作用和海马神经发生的增加有关。据我们所知，这是首次开发 ASM 的直接抑制剂来支持 ASM 作为治疗抑郁症潜在靶点的可能性。
