Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
27 10 2022
27 10 2022
Historique:
pubmed:
13
10
2022
medline:
29
10
2022
entrez:
12
10
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36222708
doi: 10.1021/acs.jmedchem.2c00515
pmc: PMC9620236
doi:
Substances chimiques
Epoxide Hydrolases
EC 3.3.2.-
Urea
8W8T17847W
Capsaicin
S07O44R1ZM
Enzyme Inhibitors
0
Analgesics
0
Cyclophosphamide
8N3DW7272P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
13660-13680Subventions
Organisme : NIEHS NIH HHS
ID : P42 ES004699
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES030443
Pays : United States
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