Abstract
The synthesis and characterization of chiral RXR selective ligands are described. The enantiomeric acids 2 and 3 were synthesized employing an enantioselective cylopropanation procedure as the key step. Compound 2, with an S,S configuration at C-9 and C-10, is a potent RXR agonist devoid of any RAR activity. The R,R enantiomer 3 is a weak RXR agonist and has demonstrable RAR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). Compound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effect at the same dosage. This further supports the contention that RXR mediated gene transcription is involved in the antidiabetic effects of RXR ligands.
MeSH terms
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Animals
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Baculoviridae / genetics
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Binding, Competitive
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Blood Glucose / metabolism
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Crystallography, X-Ray
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Fatty Acids, Unsaturated / chemical synthesis*
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Fatty Acids, Unsaturated / chemistry
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Fatty Acids, Unsaturated / metabolism
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Fatty Acids, Unsaturated / pharmacology
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / metabolism
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Hypoglycemic Agents / pharmacology
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Ligands
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Mice
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Mice, Mutant Strains
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Radioligand Assay
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Receptors, Retinoic Acid / agonists
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Receptors, Retinoic Acid / metabolism*
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Retinoid X Receptors
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Stereoisomerism
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Structure-Activity Relationship
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Tetrahydronaphthalenes / chemical synthesis*
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Tetrahydronaphthalenes / chemistry
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Tetrahydronaphthalenes / metabolism
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Tetrahydronaphthalenes / pharmacology
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Transcription Factors / agonists
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Transcription Factors / metabolism*
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Transcriptional Activation
Substances
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AGN 194204
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Blood Glucose
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Fatty Acids, Unsaturated
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Hypoglycemic Agents
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Ligands
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Tetrahydronaphthalenes
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Transcription Factors