Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors

Bioorg Med Chem. 2019 Oct 15;27(20):115078. doi: 10.1016/j.bmc.2019.115078. Epub 2019 Aug 26.

Abstract

Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.

Keywords: Adamantane; Inhibitor; Isocyanate; Soluble epoxide hydrolase; Urea.

Publication types

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Polycyclic Aromatic Hydrocarbons / chemical synthesis
  • Polycyclic Aromatic Hydrocarbons / chemistry
  • Polycyclic Aromatic Hydrocarbons / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemistry
  • Urea / pharmacology*

Substances

  • Enzyme Inhibitors
  • Polycyclic Aromatic Hydrocarbons
  • Urea
  • Epoxide Hydrolases