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.
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Codony S, Entrena JM, Calvo-Tusell C, Jora B, Gonzalez-Cano R, Osuna S, Corpas R, Morisseau C, Perez B, Barniol-Xicota M, Grinan-Ferre C, Perez C, Rodriguez-Franco MI, Martinez AL, Loza MI, Pallas M, Verhelst SHL, Sanfeliu C, Feixas F, Hammock BD, Brea J, Cobos EJ, Vazquez S (2022) Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors Journal of Medicinal Chemistry65: 13660-13680
