Codony, SandraEntrena, José MCalvó-Tusell, CarlaJora, BeatriceGonzález-Cano, RafaelOsuna, SílviaCorpas, RubénMorisseau, ChristophePérez, BelénBarniol-Xicota, MartaGriñán-Ferré, ChristianPérez, ConcepciónRodríguez-Franco, María IsabelMartínez, Antón LLoza, M IsabelPallàs, MercèVerhelst, Steven H LSanfeliu, CoralFeixas, FerranHammock, Bruce DBrea, JoséCobos, Enrique JVázquez, Santiago2023-05-032023-05-032022-10-12http://hdl.handle.net/10668/22591The 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/MiceHumansAnimalsEpoxide HydrolasesUreaDisease Models, AnimalVisceral PainCapsaicinEnzyme InhibitorsAnalgesicsCyclophosphamideresearch article36222708open access10.1021/acs.jmedchem.2c005151520-4804PMC9620236https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.2c00515https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9620236/pdf