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

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.