Abstract
The cytochrome P450 eicosanoid 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a powerful endogenous autacoid that has been ascribed an impressive array of physiologic functions including regulation of blood pressure. Because 14,15-EET is chemically and metabolically labile, structurally related surrogates containing epoxide bioisosteres were introduced and have become useful in vitro pharmacologic tools but are not suitable for in vivo applications. A new generation of EET mimics incorporating modifications to the carboxylate were prepared and evaluated for vasorelaxation and inhibition of soluble epoxide hydrolase (sEH). Tetrazole 19 (ED50 0.18 μM) and oxadiazole-5-thione 25 (ED50 0.36 μM) were 12- and 6-fold more potent, respectively, than 14,15-EET as vasorelaxants; on the other hand, their ability to block sEH differed substantially, i.e., 11 vs >500 nM. These data will expedite the development of potent and specific in vivo drug candidates.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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8,11,14-Eicosatrienoic Acid / analogs & derivatives*
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8,11,14-Eicosatrienoic Acid / chemistry
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Animals
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Cattle
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Chemistry Techniques, Synthetic
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Coronary Vessels / drug effects
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Epoxide Hydrolases / antagonists & inhibitors
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Humans
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In Vitro Techniques
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Molecular Mimicry
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology
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Oxamic Acid / analogs & derivatives
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Oxamic Acid / chemistry
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Oxamic Acid / pharmacology
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Tetrazoles / chemistry
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Tetrazoles / pharmacology
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Vasodilation / drug effects
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Vasodilator Agents / chemical synthesis
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Vasodilator Agents / chemistry*
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Vasodilator Agents / pharmacology*
Substances
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Enzyme Inhibitors
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N1-butyl-N2-(12-(2-oxido-3H-1,2,3,5-oxathiadiazol-4-yl)dodec-5-en-1-yl)oxalamide
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Oxadiazoles
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Tetrazoles
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Vasodilator Agents
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1H-tetrazole
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14,15-epoxy-5,8,11-eicosatrienoic acid
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Epoxide Hydrolases
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8,11,14-Eicosatrienoic Acid
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Oxamic Acid