Sandra Codony , José M. Entrena , Carla Calvó-Tusell , Beatrice Jora , Rafael González-Cano , Sílvia Osuna , Rubén Corpas , Christophe Morisseau , Belén Pérez , Marta Barniol-Xicota , Christian Griñán-Ferré , Concepción Pérez , María Isabel Rodríguez-Franco , Antón L. Martínez , M. Isabel Loza , Mercè Pallàs , Steven H. L. Verhelst , Coral Sanfeliu , Ferran Feixas , Bruce D. Hammock , José Brea , Enrique J. Cobos , and Santiago Vázquez
DOI: 10.1021/acs.jmedchem.2c00515
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.
