Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors

Bioorg Med Chem Lett. 2015 Apr 15;25(8):1705-1708. doi: 10.1016/j.bmcl.2015.02.076. Epub 2015 Mar 7.


We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values).

Keywords: Conformational regulation; Epoxyeicosatrienoic acids; Inhibitor; Soluble epoxide hydrolase; Three substituted cyclopropane.

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cyclopropanes / chemistry
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Humans
  • Molecular Dynamics Simulation
  • Protein Binding
  • Rats
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / metabolism


  • Cyclopropanes
  • Urea
  • cyclopropane
  • Epoxide Hydrolases