Discovery of Novel N-Hydroxy-1,2,4-oxadiazole-5-formamides as ASM Direct Inhibitors for the Treatment of Atherosclerosis,Journal of Medicinal Chemistry

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Discovery of Novel N-Hydroxy-1,2,4-oxadiazole-5-formamides as ASM Direct Inhibitors for the Treatment of Atherosclerosis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-14 , DOI: 10.1021/acs.jmedchem.2c01643
Kan Yang _{1,

2} , Keyi Nong _{1,

3} , Fei Xu ₄ , Yu Chen ₁ , Jinying Yu ₁ , Lizhi Lin ₁ , Xiao Hu ₁ , Youzhi Wang ₁ , Ting Li ₁ , Jibin Dong ₄ , Jinxin Wang ₁

Affiliation

Acid sphingomyelinase (ASM), which regulates sphingolipid metabolism and lipid signaling, has been considered as a new potential target for the treatment of atherosclerosis. In this study, a series of benzene-heterocyclic-based ASM inhibitors were rationally designed, synthesized, and screened for the first time. As a result, some compounds showed favorable inhibitory activity against recombinant human ASM. The detailed SARs are also discussed. Compound 4i revealed good pharmacokinetic data and in vivo inhibitory activity against ASM by reducing the level of ceramide in mice plasma and liver. Pharmacodynamic studies confirmed that 4i could lessen lipid plaques in the aortic arch and aorta and reduce plasma ceramide concentration and Ox-LDL levels. Moreover, 4i was found to significantly decrease LPS-induced and Ox-LDL-induced cell inflammation by regulating the levels of ceramide and sphingomyelin. Overall, this study preliminarily demonstrates that ASM may be an effective target against atherosclerosis for the first time.

中文翻译：

发现新型 N-Hydroxy-1,2,4-oxadiazole-5-formamides 作为 ASM 直接抑制剂治疗动脉粥样硬化

调节鞘脂代谢和脂质信号传导的酸性鞘磷脂酶 (ASM) 已被认为是治疗动脉粥样硬化的新潜在靶点。本研究首次合理设计、合成并筛选了一系列苯杂环类ASM抑制剂。结果，一些化合物对重组人 ASM 显示出良好的抑制活性。还讨论了详细的 SAR。化合物4i通过降低小鼠血浆和肝脏中的神经酰胺水平显示出良好的药代动力学数据和对 ASM 的体内抑制活性。药效学研究证实，4i可以减少主动脉弓和主动脉中的脂质斑块，降低血浆神经酰胺浓度和 Ox-LDL 水平。而且，4i被发现通过调节神经酰胺和鞘磷脂的水平显着减少 LPS 诱导和 Ox-LDL 诱导的细胞炎症。总体而言，本研究初步证明 ASM 可能首次成为抗动脉粥样硬化的有效靶点。

更新日期：2023-02-14

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