Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes.

摘要

In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor beta (ERbeta) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERbeta-binding affinities, with Ki values reaching the sub-nanomolar range (Ki=0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERbeta-subtype selectivity. Both compounds show a potent full agonist character on ERbeta (EC50=0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a beta/alpha transcription potency ratio 50-fold higher than that of estradiol.