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

J Med Chem. 2022 Oct 27;65(20):13660-13680. doi: 10.1021/acs.jmedchem.2c00515. Epub 2022 Oct 12.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Capsaicin
  • Cyclophosphamide
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Epoxide Hydrolases*
  • Humans
  • Mice
  • Urea / chemistry
  • Visceral Pain* / chemically induced
  • Visceral Pain* / drug therapy


  • Epoxide Hydrolases
  • Urea
  • Capsaicin
  • Enzyme Inhibitors
  • Analgesics
  • Cyclophosphamide