Journal of enzyme inhibition and medicinal chemistry · 2025
Dimethoxybenzohomoadamantane-based soluble epoxide hydrolase inhibitors: in vivo efficacy in a murine model of chemotherapy-induced neuropathic pain.
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Codony Sandra, Jora Beatrice, Santos-Caballero Miriam, Qiu Qiongju, Calvó-Tusell Carla, Escriche Celia, Turcu Andreea L, Prischi Filippo, Bartra Clara, Val Cristina, Morisseau Christophe, Pérez Belén, Bertran-Mostazo Andrea, Osuna Sílvia, Corpas Rubén, Griñán-Ferré Christian, Galdeano Carles, Loza M Isabel, Pallàs Mercè, Sanfeliu Coral, Hammock Bruce D, Brea José, Feixas Ferran, Conte Maria R, Cobos Enrique J, Vázquez Santiago
Аннотация
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.