| 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates containing epoxide bioisosteres: influence upon vascular relaxation and soluble epoxide hydrolase inhibition. | |
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MedLine Citation:
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PMID: 19653681 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 52 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2009 Aug |
Date Detail:
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Created Date: 2010-06-21 Completed Date: 2010-07-01 Revised Date: 2013-04-12 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 5069-75 Citation Subset: IM |
Affiliation:
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Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. j.falck@utsouthwestern.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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8,11,14-Eicosatrienoic Acid
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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:
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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 DK038226-220006/DK/NIDDK NIH HHS; P42 ES004699-23S2/ES/NIEHS NIH HHS; R01 13833//PHS HHS; R01 GM031278-25A1/GM/NIGMS 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:
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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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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