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

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

Research output: Contribution to journalArticle

46 Scopus citations

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 °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.

Original languageEnglish (US)
Pages (from-to)312-323
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • 1,3-disubstituted ureas
  • Pharmacokinetic properties
  • sEH inhibitors
  • Soluble epoxide hydrolase (sEH)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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    Kim, I. H., Nishi, K., Tsai, H. J., Bradford, T., Koda, Y., Watanabe, T., Morisseau, C., Blanchfield, J., Toth, I., & Hammock, B. D. (2007). Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase. Bioorganic and Medicinal Chemistry, 15(1), 312-323. https://doi.org/10.1016/j.bmc.2006.09.057