Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

J Med Chem. 2019 Sep 26;62(18):8443-8460. doi: 10.1021/acs.jmedchem.9b00445. Epub 2019 Sep 17.


The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Catalytic Domain
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / chemistry*
  • Humans
  • Ligands
  • Male
  • Oxazoles / chemistry
  • Phosphoric Monoester Hydrolases / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Temperature


  • Enzyme Inhibitors
  • Ligands
  • Oxazoles
  • Phosphoric Monoester Hydrolases
  • Epoxide Hydrolases
  • EPHX2 protein, human
  • EPHX2 protein, rat