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 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.
Vuligonda
V
V
Retinoid Research, Departments of Chemistry and Biology, Allergan Inc., 2525 Dupont Drive, Irvine, California 92623, USA. Vuligonda_Vidyasagar@Allergan.com
Thacher
S M
SM
Chandraratna
R A
RA
D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D001667:Binding, Competitive; D001786:Blood Glucose / Q000378:metabolism; D018360:Crystallography, X-Ray; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D011869:Radioligand Assay; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D047488:Retinoid X Receptors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D015533:Transcriptional Activation
C430898:AGN 194204; D001786:Blood Glucose; D005231:Fatty Acids, Unsaturated; D007004:Hypoglycemic Agents; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors