1,3-Disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic properties

In Hae Kim, Hsing Ju Tsai, Kosuke Nishi, Takeo Kasagami, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.

Original languageEnglish (US)
Pages (from-to)5217-5226
Number of pages10
JournalJournal of Medicinal Chemistry
Volume50
Issue number21
DOIs
StatePublished - Oct 18 2007

    Fingerprint

ASJC Scopus subject areas

  • Organic Chemistry

Cite this