Document Detail


14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres: influence upon vascular relaxation and soluble epoxide hydrolase inhibition.
MedLine Citation:
PMID:  19653681     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
All-cis-14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a labile, vasodilatory eicosanoid generated from arachidonic acid by cytochrome P450 epoxygenases. A series of robust, partially saturated analogues containing epoxide bioisosteres were synthesized and evaluated for relaxation of precontracted bovine coronary artery rings and for in vitro inhibition of soluble epoxide hydrolase (sEH). Depending upon the bioisostere and its position along the carbon chain, varying levels of vascular relaxation and/or sEH inhibition were observed. For example, oxamide 16 and N-iPr-amide 20 were comparable (ED(50) 1.7 microM) to 14,15-EET as vasorelaxants but were approximately 10-35 times less potent as sEH inhibitors (IC(50) 59 and 19 microM, respectively); unsubstituted urea 12 showed useful activity in both assays (ED(50) 3.5 microM, IC(50) 16 nM). These data reveal differential structural parameters for the two pharmacophores that could assist the development of potent and specific in vivo drug candidates.
Authors:
J R Falck; Ravinder Kodela; Rajkumar Manne; Krishnam Raju Atcha; Narender Puli; Narsimhaswamy Dubasi; Vijay L Manthati; Jorge H Capdevila; Xiu-Yu Yi; Daniel H Goldman; Christophe Morisseau; Bruce D Hammock; William B Campbell
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  52     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2010-06-21     Completed Date:  2010-07-01     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5069-75     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
8,11,14-Eicosatrienoic Acid / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology
Animals
Cattle
Coronary Vessels / drug effects,  physiology
Epoxide Hydrolases / antagonists & inhibitors*
Epoxy Compounds / chemical synthesis*,  chemistry,  pharmacology
Humans
Isometric Contraction / drug effects
Recombinant Proteins / antagonists & inhibitors
Solubility
Stereoisomerism
Structure-Activity Relationship
Vasodilation / drug effects*
Vasodilator Agents / chemical synthesis,  chemistry,  pharmacology
Grant Support
ID/Acronym/Agency:
DK38226/DK/NIDDK NIH HHS; ES04699/ES/NIEHS NIH HHS; GM32178/GM/NIGMS NIH HHS; HL51055/HL/NHLBI NIH HHS; HL85727/HL/NHLBI NIH HHS; P01 DK038226/DK/NIDDK NIH HHS; P01 DK038226-220006/DK/NIDDK NIH HHS; P42 ES004699/ES/NIEHS NIH HHS; P42 ES004699-23S2/ES/NIEHS NIH HHS; R01 13833//PHS HHS; R01 GM031278/GM/NIGMS NIH HHS; R01 GM031278-25A1/GM/NIGMS NIH HHS; R01 HL051055/HL/NHLBI NIH HHS; R01 HL051055-14/HL/NHLBI NIH HHS; R37 ES002710-27/ES/NIEHS NIH HHS; R37 ES02710/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Epoxy Compounds; 0/Recombinant Proteins; 0/Vasodilator Agents; 7324-41-6/8,11,14-Eicosatrienoic Acid; 81276-03-1/14,15-epoxy-5,8,11-eicosatrienoic acid; EC 3.3.2.-/Epoxide Hydrolases
Comments/Corrections

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