title: 14,15-Epoxyeicosa-5,8,11-trienoic Acid (14,15-EET) surrogates: carboxylate modifications.
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.
authors.affiliation: Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Sreenivasulu Reddy
authors.initials: SR
authors.lastname: Koduru
authors.forename: Seetaram
authors.initials: S
authors.lastname: Mohapatra
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Manne
authors.forename: Krishnam Raju
authors.initials: KR
authors.lastname: Atcha
authors.forename: Raju
authors.initials: R
authors.lastname: Atcha
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Manthati
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Capdevila
authors.forename: Sarah
authors.initials: S
authors.lastname: Christian
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D003331:Coronary Vessels / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D018716:Molecular Mimicry; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology; D010072:Oxamic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C000597430:N1-butyl-N2-(12-(2-oxido-3H-1,2,3,5-oxathiadiazol-4-yl)dodec-5-en-1-yl)oxalamide; D010069:Oxadiazoles; D013777:Tetrazoles; D014665:Vasodilator Agents; C045574:1H-tetrazole; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D010072:Oxamic Acid