Design, Synthesis and Cellular Characterization of a Dual Inhibitor of 5-Lipoxygenase and Soluble Epoxide Hydrolase

Molecules. 2016 Dec 29;22(1):45. doi: 10.3390/molecules22010045.


The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated. KM55 potently inhibited both enzymes in vitro and attenuated the formation of leukotrienes in human whole blood. KM55 was also tested in a cell function-based assay. The compound significantly inhibited the LPS-induced adhesion of leukocytes to endothelial cells by blocking leukocyte activation.

Keywords: 5-lipoxygenase; designed multitarget ligands; inflammation; leukocyte-endothelial cell interaction; soluble epoxide hydrolase.

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Arachidonic Acid / metabolism*
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hydrocarbons, Fluorinated / chemical synthesis
  • Hydrocarbons, Fluorinated / chemistry
  • Hydrocarbons, Fluorinated / pharmacology*
  • Inflammation / drug therapy
  • Leukocytes / metabolism
  • Leukotrienes / biosynthesis
  • Lipopolysaccharides
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacology


  • 1-(3-(5-(hydroxyureido)methyl-2-methoxyphenoxy)propyl)-3-(4-(trifluoromethoxy)phenyl)urea
  • Anti-Inflammatory Agents
  • Hydrocarbons, Fluorinated
  • Leukotrienes
  • Lipopolysaccharides
  • Lipoxygenase Inhibitors
  • Arachidonic Acid
  • Urea
  • Arachidonate 5-Lipoxygenase
  • Epoxide Hydrolases