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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
1998-6-15
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pubmed:abstractText |
By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid- and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl- N-h ydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Arachidonic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Furans,
http://linkedlifedata.com/resource/pubmed/chemical/Leukotriene B4,
http://linkedlifedata.com/resource/pubmed/chemical/Lipoxygenase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cell Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, G-Protein-Coupled,
http://linkedlifedata.com/resource/pubmed/chemical/Tetradecanoylphorbol Acetate,
http://linkedlifedata.com/resource/pubmed/chemical/Urea,
http://linkedlifedata.com/resource/pubmed/chemical/platelet activating factor receptor
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:CauDD,
pubmed-author:EckmanJJ,
pubmed-author:HussoinM SMS,
pubmed-author:HwangS BSB,
pubmed-author:KillianD BDB,
pubmed-author:Libertine-GarahanLL,
pubmed-author:NorMM,
pubmed-author:QianCC,
pubmed-author:ScannellR TRT,
pubmed-author:ShenT YTY,
pubmed-author:YaegerDD,
pubmed-author:YeeC LCL
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pubmed:issnType |
Print
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pubmed:day |
21
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pubmed:volume |
41
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1970-9
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:9599246-Animals,
pubmed-meshheading:9599246-Arachidonic Acid,
pubmed-meshheading:9599246-Blood Platelets,
pubmed-meshheading:9599246-CHO Cells,
pubmed-meshheading:9599246-Cell Membrane,
pubmed-meshheading:9599246-Cricetinae,
pubmed-meshheading:9599246-Drug Evaluation, Preclinical,
pubmed-meshheading:9599246-Edema,
pubmed-meshheading:9599246-Enzyme Inhibitors,
pubmed-meshheading:9599246-Furans,
pubmed-meshheading:9599246-Hematocrit,
pubmed-meshheading:9599246-Humans,
pubmed-meshheading:9599246-Leukotriene B4,
pubmed-meshheading:9599246-Lipoxygenase Inhibitors,
pubmed-meshheading:9599246-Mice,
pubmed-meshheading:9599246-Platelet Membrane Glycoproteins,
pubmed-meshheading:9599246-Rats,
pubmed-meshheading:9599246-Receptors, Cell Surface,
pubmed-meshheading:9599246-Receptors, G-Protein-Coupled,
pubmed-meshheading:9599246-Structure-Activity Relationship,
pubmed-meshheading:9599246-Tetradecanoylphorbol Acetate,
pubmed-meshheading:9599246-Tumor Cells, Cultured,
pubmed-meshheading:9599246-Urea
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pubmed:year |
1998
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pubmed:articleTitle |
(+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4, 5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a potent dual 5-lipoxygenase inhibitor and platelet-activating factor receptor antagonist.
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pubmed:affiliation |
CytoMed, Inc., 840 Memorial Drive, Cambridge, Massachusetts 02139, and Department of Chemistry, University of Virginia, Charlottesville, Virginia 22903, USA.
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pubmed:publicationType |
Journal Article
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