Importance of the field: Nonsteroidal estrogens have been known since the 1930s. However, the relatively recent (1996) discovery of estrogen receptor subtype beta (ERbeta) suggested a possible paradigm shift away from SERM-like selectivity. Selective ERbeta agonism would potentially allow expansion of estrogenic targeting into new indications (discussed herein) currently precluded by the thrombogenic and hyperproliferative effects of nonselective estrogens.
Areas covered in this review: ERbeta agonist design has been very successful. Pharmacophores for ERbeta selective nonsteroidal estrogens are generally diphenolic compounds that achieve an inter-phenolic distance and geometry similar to 17beta-estradiol with few restraints on the nature of the element linking the phenols (or phenol mimetics). The tremendously chemodiverse ERbeta agonist patent literature is reviewed, segregating the agonists into structurally similar compounds based on their interphenolic linking elements.
What the reader will gain: A comprehensive understanding of the chemotype landscape of this field and an assessment of its maturation.
Take home message: Subtype selective ERbeta agonist therapy seems very promising. However, more clinical testing is needed to firmly establish its therapeutic potential. At this point, ERbeta is a promising target in search of an indication.