Evaluation of 17alpha-E-(trifluoromethylphenyl)vinyl estradiols as novel estrogen receptor ligands

As part of our program to develop novel ligands for the estrogen receptor, we synthesized the series of isomeric 17alpha-(trifluoromethyl)phenylvinyl estradiols using our solid-phase organic synthesis methodology. The compounds were evaluated for their relative binding affinity (RBA) using the ERalpha-LBD and in vivo potency using the immature rat uterotrophic growth assay. The ortho-isomer had the highest RBA values, 48-223, and the highest estrogenicity in vivo. The other isomers had significantly lower affinities and were weaker agonists in the uterotrophic assay. The results suggest that introduction of substituents at the 17alpha-position of estradiol is tolerated by the ER-LBD and permit agonist responses in the intact animal, however, the effect is sensitive to the position of groups on the phenyl ring. This study demonstrates that the 17alpha-position of estradiol is a reasonable site for modification but the position and physicochemical properties of such modifications may significantly affect the affinity and efficacy of the ligand.