SYNTHESES AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL RETINOID-X-RECEPTOR AGONISTS

As part of our studies to develop novel retinoids with increased affin ity and selectivity for the retinoid X receptor (RXR) subfamily, we ha ve designed and synthesized a series of 6-yl)-7-alky-6-fluoro-3-methyl hepta-2,4,6-trienoic acid derivatives. These tetrahydroquinolines, gen erated by introducing a polar N atom into the hydrophobic part of the retinoid skeleton, showed high binding affinity to RXRs. Addition of f luorine at the 6-position of the 2,4,6-trienoic acid moiety afforded c ompounds which elicit potent and selective transactivation of the RXRs . Compound 14b (ER-35794), which possesses an ethyl substituent at the 7-position and fluorine at the 6-position of the triene moiety, is on e of the most potent and selective RXR agonists reported to date.