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.
Codony S, Pont C, Grinan-Ferre C, Di Pede-Mattatelli A, Calvo-Tusell C, Feixas F, Osuna S, Jarne-Ferrer J, Naldi M, Bartolini M, Loza MI, Brea J, Perez B, Bartra C, Sanfeliu C, Juarez-Jimenez J, Morisseau C, Hammock BD, Pallas M, Vazquez S, Munoz-Torrero D, Entrena JM, Jora B, Gonzalez-Cano R, Corpas R, Barniol-Xicota M, Perez C, Rodriguez-Franco MI, Martinez AL, Verhelst SHL, Cobos EJ (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 Chemistry
Codony S, Pont C, Grinan-Ferre C, Di Pede-Mattatelli A, Calvo-Tusell C, Feixas F, Osuna S, Jarne-Ferrer J, Naldi M, Bartolini M, Loza MI, Brea J, Perez B, Bartra C, Sanfeliu C, Juarez-Jimenez J, Morisseau C, Hammock BD, Pallas M, Vazquez S, Munoz-Torrero D, Entrena JM, Jora B, Gonzalez-Cano R, Corpas R, Barniol-Xicota M, Perez C, Rodriguez-Franco MI, Martinez AL, Verhelst SHL, Cobos EJ (2022) Journal of Medicinal Chemistry
