Dimethoxybenzohomoadamantane-based soluble epoxide hydrolase inhibitors: in vivo efficacy in a murine model of chemotherapy-induced neuropathic pain.

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-10-23 DOI:10.1080/14756366.2025.2574990

Sandra Codony, Beatrice Jora, Miriam Santos-Caballero, Qiongju Qiu, Carla Calvó-Tusell, Celia Escriche, Andreea L Turcu, Filippo Prischi, Clara Bartra, Cristina Val, Christophe Morisseau, Belén Pérez, Andrea Bertran-Mostazo, Sílvia Osuna, Rubén Corpas, Christian Griñán-Ferré, Carles Galdeano, M Isabel Loza, Mercè Pallàs, Coral Sanfeliu, Bruce D Hammock, José Brea, Ferran Feixas, Maria R Conte, Enrique J Cobos, Santiago Vázquez

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引用次数: 0

Abstract

The soluble epoxide hydrolase (sEH) has recently emerged as a promising target for the treatment of several pain-related conditions. Herein, we report the design and synthesis of a peripherally restricted sEH inhibitor with high potency and good Drug Metabolism and Pharmacokinetics (DMPK) properties. Molecular dynamics and X-ray crystallography helped reveal the binding of these inhibitors to sEH. The selected compound showed a robust analgesic effect in a dose-dependent manner in a murine model of chemotherapy-induced neuropathic pain (CINP). Moreover, the compound also prevented the development of paclitaxel-induced neuropathic pain. Overall, these results suggest that peripheral inhibition of sEH might constitute a novel therapy to prevent and treat CINP.

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基于二甲氧基苯并同源金刚烷的可溶性环氧化物水解酶抑制剂：在化疗引起的神经性疼痛小鼠模型中的体内疗效。

可溶性环氧化物水解酶（sEH）最近成为治疗几种疼痛相关疾病的有希望的靶点。在此，我们报道了一种高效和良好的药物代谢和药代动力学（DMPK）特性的外周限制性sEH抑制剂的设计和合成。分子动力学和x射线晶体学有助于揭示这些抑制剂与sEH的结合。所选化合物在小鼠化疗诱导的神经性疼痛（CINP）模型中显示出剂量依赖的强大镇痛作用。此外，该化合物还可以防止紫杉醇引起的神经性疼痛的发展。总之，这些结果表明外周抑制sEH可能是预防和治疗CINP的一种新疗法。

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来源期刊

Journal of Enzyme Inhibition and Medicinal Chemistry 医学-生化与分子生物学

CiteScore

10.30

自引率

10.70%

发文量

195

审稿时长

4-8 weeks

期刊介绍： Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.