2022, Codony, Sandra, Entrena, José M., Calvó-Tusell, Carla, Jora, Beatrice, González-Cano, Rafael, Osuna, Sílvia, Corpas, Rubén, Morisseau, Christophe, Pérez, Belén, Barniol-Xicota, Marta, Griñán-Ferré, Christian, Pérez, Concepción, Rodríguez-Franco, María Isabel, Martínez, Antón L., Loza, M. Isabel, Pallàs, Mercè, Verhelst, Steven H. L., Sanfeliu, Coral, Feixas, Ferran, Hammock, Bruce D., Brea, José, Cobos, Enrique J., Vázquez, Santiago

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.