Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

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

Authors: Kim, In-Hae; Tsai, Hsing-Ju; Nishi, Kosuke; Kasagami, Takeo; Morisseau, Christophe; Hammock, Bruce D

Published In J Med Chem, (2007 Oct 18)

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.

PubMed ID: 17894481 Exiting the NIEHS site

MeSH Terms: Adamantane/analogs & derivatives; Adamantane/chemical synthesis; Adamantane/pharmacokinetics; Adamantane/pharmacology; Animals; Cyclohexanes/chemical synthesis; Cyclohexanes/pharmacokinetics; Cyclohexanes/pharmacology; Dogs; Epoxide Hydrolases/antagonists & inhibitors*; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Mice; Microsomes, Liver/metabolism; Phenylurea Compounds/chemical synthesis; Phenylurea Compounds/pharmacokinetics; Phenylurea Compounds/pharmacology; Rats; Solubility; Structure-Activity Relationship; Urea/analogs & derivatives*; Urea/chemical synthesis*; Urea/pharmacokinetics; Urea/pharmacology

Back
to Top