Discovery of 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating of chronic kidney diseases

Bioorg Med Chem Lett. 2014 Jan 15;24(2):565-70. doi: 10.1016/j.bmcl.2013.12.020. Epub 2013 Dec 10.

Abstract

We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity and bioavailability. When administered orally at 30 mg/kg, 19 lowered serum creatinine in a rat model of anti-glomerular basement membrane glomerulonephritis but 2,8-diazaspiro[4.5]decane-based trisubstituted ureas did not. These results suggest that 19 is an orally active drug candidate for treating chronic kidney diseases.

Keywords: Anti-GBM glomerulonephritis rat model; Chronic kidney diseases; Spirocyclic diamine; Urea; sEH inhibitor.

MeSH terms

  • Administration, Oral
  • Alkanes / administration & dosage
  • Alkanes / chemistry*
  • Animals
  • Drug Discovery / methods*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Humans
  • Rats
  • Renal Insufficiency, Chronic / drug therapy
  • Renal Insufficiency, Chronic / enzymology*
  • Solubility
  • Structure-Activity Relationship
  • Urea / administration & dosage
  • Urea / analogs & derivatives*

Substances

  • Alkanes
  • Urea
  • Epoxide Hydrolases
  • undecane