Enantioselective syntheses of potent retinoid X receptor ligands: Differential biological activities of individual antipodes

The synthesis and characterization of chiral RXR selective ligands are desc ribed. The enantiomeric acids 2 and 3 were synthesized employing an enantio selective 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 R AR activity in the receptor transactivation assays. The potent RXR activity of 2 was further confirmed in a hyperglycemic animal model (db/db mice). C ompound 2 lowered glucose by 50% by day 7 at 2 mg/kg, whereas 3 had no effe ct at the same dosage. This further supports the contention that RXR mediat ed gene transcription is involved in the antidiabetic effects of RXR ligand s.