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: Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase.

Authors: Kim, In-Hae; Nishi, Kosuke; Tsai, Hsing-Ju; Bradford, Tanya; Koda, Yasuko; Watanabe, Takaho; Morisseau, Christophe; Blanchfield, Joanne; Toth, Istvan; Hammock, Bruce D

Published In Bioorg Med Chem, (2007 Jan 1)

Abstract: The soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in blood pressure regulation and vascular inflammation. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid (AUDA, 1) is a very active inhibitor of sEH both in vitro and in vivo. However, its relatively high melting point and limited solubility in either water or oil-based solvents leads to difficulties in formulating the compound and often results in poor in vivo availability. We investigated the effect of derivatization of the acid functional group of inhibitor 1 on the inhibition potencies, physical properties, and pharmacokinetic properties. For human sEH, similar inhibition potency was obtained when the acid of compound 1 was modified to esters (2-15). The resulting compounds exhibited improved physical properties (23-66 degrees C lower melting point and 5-fold better solubility in oil). Pharmacokinetic studies showed that the esters possess improved oral bioavailability in mice. On the other hand, amide derivatives of AUDA 1 did not show significant improvement in inhibition potencies or physical properties (higher melting points and lower solubility). The esterification of 1 results in compounds that are easier to formulate in animal food and in triglycerides for gavage and other routes of administration, making it easier to study the biological effects of sEH inhibition in vivo.

PubMed ID: 17046265 Exiting the NIEHS site

MeSH Terms: Adamantane/administration & dosage; Adamantane/analogs & derivatives*; Adamantane/chemical synthesis; Adamantane/pharmacology; Administration, Oral; Animals; Drug Design; Enzyme Inhibitors/administration & dosage; Enzyme Inhibitors/chemical synthesis*; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Humans; Lauric Acids/administration & dosage; Lauric Acids/chemical synthesis*; Lauric Acids/pharmacology*; Male; Mice; Molecular Structure; Solubility; Stereoisomerism; Structure-Activity Relationship; Time Factors; Tissue Distribution

Back
to Top