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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2003-6-12
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pubmed:abstractText |
Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases in triglycerides and profound suppression of the thyroid hormone axis. Here we describe the design and synthesis of new RXR modulators that retain the insulin-sensitizing activity of RXR agonists but produce substantially reduced side effects. These molecules bind selectively and with high affinity to RXR and, unlike RXR agonists, do not activate RXR homodimers. To further evaluate the antidiabetic activity of these RXR modulators, we have designed a concise and systematic structure-activity relationship around the 2E,4E,6Z-7-aryl-3-methylocta-2,4,6-trienoic acid scaffold. Selected compounds have been evaluated using insulin-resistant rodents (db/db mice) to characterize effects on glucose homeostasis. Our studies demonstrate the effectiveness of RXR modulators in lowering plasma glucose in the db/db mouse model.
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:ArdeckyR JRJ,
pubmed-author:BoehmM FMF,
pubmed-author:ChenJ HJH,
pubmed-author:CrombieD LDL,
pubmed-author:EtgenG JGJ,
pubmed-author:FaulM MMM,
pubmed-author:FaulknerA LAL,
pubmed-author:GreseT ATA,
pubmed-author:HeymanR ARA,
pubmed-author:KaranewskyD SDS,
pubmed-author:KlausingKK,
pubmed-author:LeibowitzM DMD,
pubmed-author:LiuSS,
pubmed-author:MaisD ADA,
pubmed-author:MapesC MCM,
pubmed-author:MarschkeK BKB,
pubmed-author:MichellysP YPY,
pubmed-author:OgilvieK MKM,
pubmed-author:Reifel-MillerAA,
pubmed-author:RungtaDD,
pubmed-author:ThompsonA WAW,
pubmed-author:TyhonasJ SJS
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
46
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2683-96
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pubmed:dateRevised |
2004-11-17
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pubmed:meshHeading |
pubmed-meshheading:12801232-Animals,
pubmed-meshheading:12801232-Blood Glucose,
pubmed-meshheading:12801232-Diabetes Mellitus, Type 2,
pubmed-meshheading:12801232-Hypoglycemic Agents,
pubmed-meshheading:12801232-Insulin Resistance,
pubmed-meshheading:12801232-Male,
pubmed-meshheading:12801232-Mice,
pubmed-meshheading:12801232-Octanoic Acids,
pubmed-meshheading:12801232-Radioligand Assay,
pubmed-meshheading:12801232-Rats,
pubmed-meshheading:12801232-Rats, Sprague-Dawley,
pubmed-meshheading:12801232-Receptors, Retinoic Acid,
pubmed-meshheading:12801232-Retinoid X Receptors,
pubmed-meshheading:12801232-Structure-Activity Relationship,
pubmed-meshheading:12801232-Transcription Factors
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pubmed:year |
2003
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pubmed:articleTitle |
Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of type 2 diabetes.
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pubmed:affiliation |
Department of Medicinal Chemistry, Ligand Pharmaceuticals, Incorporated, 10275 Science Center Drive, San Diego, California 92121, USA. pmichellys@ligand.com
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pubmed:publicationType |
Journal Article
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