Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors.
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| Abstract |
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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| Authors | 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, Santiago Vázquez |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 20 Pg. 13660-13680 (10 27 2022) ISSN: 1520-4804 [Electronic] United States |
| PMID | 36222708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural) |
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