Orally bioavailable potent soluble epoxide hydrolase inhibitors

Hee Hwang Sung, Hsing Ju Tsai, Jun Yan Liu, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

A series of N,N′-disubstituted ureas having a conformationally restricted cis- or trans-1,4-cyclohexane α to the urea were prepared and tested as soluble epoxide hydrolase (sEH) inhibitors. This series of compounds showed low nanomolar to picomolar activities against recombinant human sEH. Both isomers showed similar potencies, but the trans isomers were more metabolically stable in human hepatic microsomes. Furthermore, these new potent inhibitors show a greater metabolic stability in vivo than previously described sEH inhibitors. We demonstrated that trans-4-[4-(3-adamantan-1-ylureido) cyclohexyloxy]benzoic acid 13g (t-AUCB, IC50 = 1.3 ± 0.05 nM) had excellent oral bioavailability (98%, n = 2) and blood area under the curve in dogs and was effective in vivo to treat hypotension in lipopolysaccharide challenged murine models.

Original languageEnglish (US)
Pages (from-to)3825-3840
Number of pages16
JournalJournal of Medicinal Chemistry
Volume50
Issue number16
DOIs
StatePublished - Aug 9 2007

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Epoxide Hydrolases
Isomers
Urea
Microsomes
Hypotension
Biological Availability
Inhibitory Concentration 50
Area Under Curve
Lipopolysaccharides
Blood
Dogs
Liver
4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Sung, H. H., Tsai, H. J., Liu, J. Y., Morisseau, C., & Hammock, B. D. (2007). Orally bioavailable potent soluble epoxide hydrolase inhibitors. Journal of Medicinal Chemistry, 50(16), 3825-3840. https://doi.org/10.1021/jm070270t

Orally bioavailable potent soluble epoxide hydrolase inhibitors. / Sung, Hee Hwang; Tsai, Hsing Ju; Liu, Jun Yan; Morisseau, Christophe; Hammock, Bruce D.

In: Journal of Medicinal Chemistry, Vol. 50, No. 16, 09.08.2007, p. 3825-3840.

Research output: Contribution to journalArticle

Sung, HH, Tsai, HJ, Liu, JY, Morisseau, C & Hammock, BD 2007, 'Orally bioavailable potent soluble epoxide hydrolase inhibitors', Journal of Medicinal Chemistry, vol. 50, no. 16, pp. 3825-3840. https://doi.org/10.1021/jm070270t
Sung HH, Tsai HJ, Liu JY, Morisseau C, Hammock BD. Orally bioavailable potent soluble epoxide hydrolase inhibitors. Journal of Medicinal Chemistry. 2007 Aug 9;50(16):3825-3840. https://doi.org/10.1021/jm070270t
Sung, Hee Hwang ; Tsai, Hsing Ju ; Liu, Jun Yan ; Morisseau, Christophe ; Hammock, Bruce D. / Orally bioavailable potent soluble epoxide hydrolase inhibitors. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 16. pp. 3825-3840.
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