Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 16, Pages 3825-3840Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm070270t
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Funding
- NIEHS NIH HHS [P30 ES 05707, P42 ES 04699, R01 ES002710, P30 ES005707, R37 ES002710-27, ES 02710, P42 ES004699-21, P30 ES005707-119017, P42 ES004699, R37 ES002710] Funding Source: Medline
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A series of N,N'-disubstituted ureas having a conformationally restricted cis- or traiis-1,4-cyclohexane alpha 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.
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