Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs

Hsing Ju Tsai, Sung Hee Hwang, Christophe Morisseau, Jun Yang, Paul D. Jones, Takeo Kasagami, In Hae Kim, Bruce D. Hammock

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,. N'-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1. mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.

Original languageEnglish (US)
Pages (from-to)222-238
Number of pages17
JournalEuropean Journal of Pharmaceutical Sciences
Volume40
Issue number3
DOIs
StatePublished - Jun 2010

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Keywords

  • Bioavailability
  • Cardiovascular diseases
  • Epoxyeicosatrienoic acids
  • Inflammation
  • Pharmacokinetics
  • Soluble epoxide hydrolase inhibitor

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Tsai, H. J., Hwang, S. H., Morisseau, C., Yang, J., Jones, P. D., Kasagami, T., Kim, I. H., & Hammock, B. D. (2010). Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs. European Journal of Pharmaceutical Sciences, 40(3), 222-238. https://doi.org/10.1016/j.ejps.2010.03.018