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Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors
- 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 HL;
- Sanfeliu, Coral;
- Feixas, Ferran;
- Hammock, Bruce D;
- Brea, José;
- Cobos, Enrique J;
- Vázquez, Santiago
- et al.
Published Web Location
https://doi.org/10.1021/acs.jmedchem.2c00515Abstract
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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