Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors
Metadatos
Afficher la notice complèteAuteur
Codony, Sandra; Entrena Fernández, José Manuel; González Cano, Rafael; Cobos del Moral, Enrique JoséEditorial
American Chemical Society
Date
2022-10-12Referencia bibliográfica
J. Med. Chem. 2022, 65, 13660−13680. [https://doi.org/10.1021/acs.jmedchem.2c00515]
Patrocinador
Spanish Government SAF2017-82771-R RTI2018-093955-B-C21 PGC2018-102192-B-I00 RTI2018-101032-J-I00 Spanish MCIN/AEI; ERDF A way of making Europe - MCIN/AEI PID2020-118127RB-I00; PID2019-106285RB; ERDF A way of making Europe; Xunta de Galicia; European Commission ED431G 2019/02; ED431C 2018/21; Fundacio Bosch i Gimpera; Universitat de Barcelona (F2I grant) Generalitat de Catalunya 2017 SGR 106 2017 SGR 1707; European Research Council (ERC) European Commission ERC-2015-StG-679001-NetMoDEzyme European Commission MSCA-IF-2014-EF661160-MetAccembly; Universitat de Barcelona (APIF grant); Spanish Society of Medicinal Chemistry (SEQT) and Lilly FWO 12Y0720N; Ministry of Science and Innovation, Spain (MICINN) Spanish Government RYC2020-029552-I; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R35 ES03443 P42 ES004699; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Neurological Disorders & Stroke (NINDS) R01 DK107767 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01 DK103616Résumé
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.