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, Jose M; Calvo-Tusell, Carla; Jora, Beatrice; Gonzalez-Cano, Rafael; Osuna, Silvia; Corpas, Ruben; Morisseau, Christophe; Perez, Belen; Barniol-Xicota, Marta; Grinan-Ferre, Christian; Perez, Concepcion; Isabel Rodriguez-Franco, Maria; Martinez, Anton L; Isabel Loza, M; Pallas, Merce; Verhelst, Steven HL; Sanfeliu, Coral; Feixas, Ferran; Hammock, Bruce D; Brea, Jose; Cobos, Enrique J; Vazquez, Santiago

doi:10.1021/acs.jmedchem.2c00515

Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

Author:

Codony, Sandra

Entrena, Jose M ; Calvo-Tusell, Carla ; Jora, Beatrice ; Gonzalez-Cano, Rafael ; Osuna, Silvia ; Corpas, Ruben ; Morisseau, Christophe ; Perez, Belen ; Barniol-Xicota, Marta ; Grinan-Ferre, Christian ; Perez, Concepcion ; Isabel Rodriguez-Franco, Maria ; Martinez, Anton L ; Isabel Loza, M ; Pallas, Merce ; Verhelst, Steven HL ; Sanfeliu, Coral ; Feixas, Ferran ; Hammock, Bruce D ; Brea, Jose ; Cobos, Enrique J ; Vazquez, Santiago

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, ARACHIDONIC-ACID METABOLISM, NMDA RECEPTOR ANTAGONIST, MOLECULAR-DYNAMICS, EPOXYEICOSATRIENOIC ACIDS, BIOLOGICAL EVALUATION, ATOMIC CHARGES, PHARMACOKINETICS, SORAFENIB, SYSTEM, SINGLE, Mice, Humans, Animals, Epoxide Hydrolases, Urea, Disease Models, Animal, Visceral Pain, Capsaicin, Enzyme Inhibitors, Analgesics, Cyclophosphamide, 12Y0720N#55264053, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

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.