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

Abstract

In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) 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 ERβ-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 ERβ-subtype selectivity. Both compounds show a potent full-agonist character on ERβ (EC50 = 0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype-selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.

Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test

“…DPN, EPB-041, WAY-202196, WAY-200070 and 8b-VE 2 are all at least 70-fold selective for ERb over ERa based on ligand binding data and the potencies of these compounds range from 18 to 180% that of 17b-estradiol (Meyers et al, 2001;Malamas et al, 2004;Mewshaw et al, 2005;Harris, 2007;Bertini et al, 2011). Both SERM-beta1 and 2 compare favorably in terms of their binding selectivity for human ERb with selectivity of well over 100-fold higher affinity as compared to that for ERa.…”

“…Some of these include caffeic acid phenethyl ester (Jung et al, 2010), butyl 4-(butyryloxy) benzoate (Lin et al, 2008), the diarylpropionitriles (Meyers et al, 2001), the aryl diphenolic azoles and the benzoazole ERB-041 (Malamas et al, 2004;Follettie et al, 2006), genistein derivatives (Mewshaw et al, 2005), effusol derivatives (e.g., benzo[c]chromenone analogs) (Sun et al, 2006), salicylaldoximes (Bertini et al, 2011) and the tetrahydrofluorenones (Parker et al, 2006;Wilkening et al, 2006).…”

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

“…8). These two oxime derivatives display a very interesting profile of both ERβ affinity and selectivity ( 38 : ERβ-RBA = 130 %, β/α= 29, 39 : ERβ-RBA = 87.1 %, β/α= 46), and profiled as full agonist on ERβ, with a remarkable beta-selectivity in the functional assays [116]. In particular, ERβ-EC 50 values were found to be 0.23 nM for 38 and 1.3 nM for 39 .…”

Steroid Hormones and Ovarian Cancer

“…Benzopyran-derived selective estrogen receptor beta-agonist-1 (SERBA-1) is a selective ER receptor agonist which has been studied in mice and prostate hyperplasia, with promising effects (Norman et al, 2006). Monoaryl-substituted salicylaldoximes also show high ER affinity and are interesting new compounds (Bertini et al, 2011). The role of exogenous hormones in ovarian cancer also remains unclear.…”