Design and Synthesis of Dual-Targeting Inhibitors of sEH and HDAC6 for the Treatment of Neuropathic Pain and Lipopolysaccharide-Induced Mortality.

sEH 和 HDAC6 双靶向抑制剂的设计和合成 ， 用于治疗神经性疼痛和脂多糖诱导的死亡率。

• 影响指数: 8.039
• 发表时间: 2024 Feb 8
• 来源期刊: J Med Chem
• DOI: 10.1021/acs.jmedchem.3c02006
• PMID: 38236416
• 文章类型: Journal Article
• 中科院分区: Q1
• 方向: 医学
• 作者列表: Chen Y,Sun J,Tong H,Wang J,Cao R,Xu H,Chen L,Morisseau C,Zhang M,Shi Y,Han C,Zhuang J,Jing Y,Liu Z,Hammock BD,Chen G

Mesh: Animals; Mice; Analgesics / pharmacology therapeutic use; Epoxide Hydrolases / antagonists & inhibitors; Gabapentin; Histone Deacetylase 6 / antagonists & inhibitors; Lipopolysaccharides / pharmacology; Neuralgia / chemically induced drug therapy; Histone Deacetylase Inhibitors / chemistry pharmacology

Abstract

Epoxyeicosatrienoic acids with anti-inflammatory effects are inactivated by soluble epoxide hydrolase (sEH). Both sEH and histone deacetylase 6 (HDAC6) inhibitors are being developed as neuropathic pain relieving agents. Based on the structural similarity, we designed a new group of compounds with inhibition of both HDAC6 and sEH and obtained compound M9. M9 exhibits selective inhibition of HDAC6 over class I HDACs in cells. M9 shows good microsomal stability, moderate plasma protein binding rate, and oral bioavailability. M9 exhibited a strong analgesic effect in vivo, and its analgesic tolerance was better than gabapentin. M9 improved the survival time of mice treated with lipopolysaccharide (LPS) and reversed the levels of inflammatory factors induced by LPS in mouse plasma. M9 represents the first sEH/HDAC6 dual inhibitors with in vivo antineuropathic pain and anti-inflammation.

摘要

具有抗炎作用的环氧二十碳三烯酸被可溶性环氧化物水解酶（sEH）灭活。sEH和组蛋白脱乙酰酶6（HDAC6）抑制剂均被开发为神经性疼痛缓解剂。基于结构相似性,我们设计了一组同时抑制HDAC6和sEH的新化合物，并获得了化合物M9。M9在细胞中显示HDAC6相对于I类HDAC的选择性抑制。M9表现出良好的微粒体稳定性,中等血浆蛋白结合率，和口服生物利用度。M9在体内表现出强烈的镇痛作用，镇痛耐受性优于加巴喷丁。M9提高了脂多糖(LPS)处理小鼠的存活时间,逆转了LPS诱导的小鼠血浆中炎症因子的水平。M9代表第一种具有体内抗神经性疼痛和抗炎作用的sEH/HDAC6双重抑制剂。