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.
orcId Calvó-Tusell, Carla​ ​ ​ ​
Calvó-Tusell, Carla
​ ​ ​ ​
Jora, Beatrice
​ ​ ​ ​
González-Cano, Rafael
orcId Osuna Oliveras, Sílvia​ researcherId Osuna Oliveras, Sílvia​ scopusId Osuna Oliveras, Sílvia​ ​
Osuna Oliveras, 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 H.L.
​ ​ ​ ​
Sanfeliu, Coral
orcId Feixas Geronès, Ferran​ researcherId Feixas Geronès, Ferran​ scopusId Feixas Geronès, Ferran​ ​
Feixas Geronès, Ferran
​ ​ ​ ​
Hammock, Bruce D.
​ ​ ​ ​
Brea, José
​ ​ ​ ​
Cobos, Enrique J.
​ ​ ​ ​
Vázquez, Santiago
Text Complet
acs.jmedchem.2c00515.pdf 5.506  Mb | PDF ​
​
Compartir
​
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 ​
Aquest document està subjecte a una llicència Creative Commons:Reconeixement (by) Creative Commons by4.0
Mostra el registre complet de l'element