Abstract
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
MeSH terms
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Alkenes / chemistry
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Alkenes / pharmacology
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Animals
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Benzene Derivatives / chemical synthesis
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Benzene Derivatives / chemistry*
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Benzene Derivatives / pharmacology*
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Caprylates / chemical synthesis
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Caprylates / chemistry*
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Caprylates / pharmacology*
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Cell Line
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Chlorocebus aethiops
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Dose-Response Relationship, Drug
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Drug Design
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Drug Synergism
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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Male
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Mice
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Retinoic Acid / agonists
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Receptors, Retinoic Acid / antagonists & inhibitors
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism
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Retinoid X Receptors
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Rosiglitazone
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Structure-Activity Relationship
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Thiazoles / pharmacology
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Thiazolidinediones*
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Thyroxine / blood
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Transcription Factors / agonists
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transfection
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Triglycerides / blood
Substances
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Alkenes
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Benzene Derivatives
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Caprylates
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Hypoglycemic Agents
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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Triglycerides
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Rosiglitazone
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Thyroxine