Selective activators of estrogen receptor beta based on the aldoxime and ketoxime scaffolds

Estrogen receptor beta (ERβ) was discovered in 1996 and, since then, there continues to be a growing list of confirmed and potential therapeutic uses for ERβ-selective ligands. There is evidence that an imbalanced expression of ERβ might play a key role in the development and progression of many tumor types. In particular, ERβ shows a general anti-proliferative and pro-apoptotic effect in various cancers, such as breast, colon, prostate, ovarian and gliomas. Besides, many of the estrogenic beneficial effects in pre-menopausal women, such as neuro- and cardio-protection, seem to be mediated by ERβ-activation. Since ERβ-agonists generally show few side effects, identification of this type of compounds that possess optimized drug-like properties as therapeutic agents can be readily extended to clinical use against the above-mentioned pathologies. Over the past few years, we have reported on new classes of salicylaldoxime-based ERβ-agonists (Salaldox A and B) displaying good selectivity levels in both binding affinity and transcriptional activation assays. We have now developed new ketoxime-based ERβ-ligands, which show an enhanced selectivity in the functional activation of the beta-subtype. These compounds have the potential of being further developed to cover clinical needs that are still unmet by currently available therapies, by means of selective ERβ-activation.