Search

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.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.A comprehensive understanding of the chemotype landscape of this field and an assessment of its maturation.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.

The androgen receptor (AR) is a nuclear hormone receptor that, upon binding to testosterone, dihydrotestosterone (DHT) and other endogenous androgens, supports the development, growth and maintenance of masculine features through activation of anabolic and androgenic metabolism. The AR has been demonstrated to be a productive therapeutic target. AR ligands in clinical practice include androgenic steroids, antiandrogenic steroids and antiandrogenic nonsteroidals. Of primary importance for this review are nonsteroidal selective AR modulators (SARMs) that have tissue-specific agonist and/or antagonist activities. The AR has a myriad of peripheral and central functions that can be modulated in a pleiotropic and tissue-specific fashion using the increasingly diverse collection of SARMs discussed herein. This suggests that SARMs will have a high level of clinical utility for a wide variety of health conditions. The patent literature focusing on SARMs is reviewed and reveals multiple chemical classes in various ...