Orally Bioavailable Potent Soluble Epoxide Hydrolase Inhibitors

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 isom...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-08, Vol.50 (16), p.3825-3840
Main Authors: Hwang, Sung Hee, Tsai, Hsing-Ju, Liu, Jun-Yan, Morisseau, Christophe, Hammock, Bruce D
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adamantane - chemical synthesis
Adamantane - pharmacokinetics
Administration, Oral
Animals
Benzoates - chemical synthesis
Benzoates - pharmacokinetics
Biological and medical sciences
Biological Availability
Cats
Cricetinae
Dogs
Epoxide Hydrolases - antagonists & inhibitors
Epoxide Hydrolases - chemistry
Humans
Hypotension - chemically induced
Hypotension - drug therapy
In Vitro Techniques
Lipopolysaccharides
Male
Medical sciences
Mice
Mice, Inbred C57BL
Microsomes, Liver - metabolism
Miscellaneous
Models, Molecular
Pharmacology. Drug treatments
Rats
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - chemistry
Solubility
Species Specificity
Stereoisomerism
Structure-Activity Relationship
Urea - analogs & derivatives
Urea - chemical synthesis
Urea - pharmacokinetics
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070270t