Enantioselective Syntheses of Potent Retinoid X Receptor Ligands:  Differential Biological Activities of Individual Antipodes

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-07, Vol.44 (14), p.2298-2303
Main Authors: Vuligonda, Vidyasagar, Thacher, Scott M, Chandraratna, Roshantha A. S
Format: Article
Language:English
Subjects:
Animals
Baculoviridae - genetics
Binding, Competitive
Biological and medical sciences
Blood Glucose - metabolism
Crystallography, X-Ray
Fatty Acids, Unsaturated - chemical synthesis
Fatty Acids, Unsaturated - chemistry
Fatty Acids, Unsaturated - metabolism
Fatty Acids, Unsaturated - pharmacology
General and cellular metabolism. Vitamins
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - metabolism
Hypoglycemic Agents - pharmacology
Ligands
Medical sciences
Mice
Mice, Mutant Strains
Pharmacology. Drug treatments
Radioligand Assay
Receptors, Retinoic Acid - agonists
Receptors, Retinoic Acid - metabolism
Retinoid X Receptors
Stereoisomerism
Structure-Activity Relationship
Tetrahydronaphthalenes - chemical synthesis
Tetrahydronaphthalenes - chemistry
Tetrahydronaphthalenes - metabolism
Tetrahydronaphthalenes - pharmacology
Transcription Factors - agonists
Transcription Factors - metabolism
Transcriptional Activation
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0100584