Novel core scaffolds for the development of subtype selective estrogen receptor ligands

There are two known estrogen receptor ER subtypes, ERalpha and ERbeta. They are present in both men and women and have been implicated as a pharmaceutical target for the treatment of breast cancer, prostate cancer and osteoporosis. Although the subtypes have been identified their physiological role is not fully understood, especially in cells where both subtypes are present. The development of novel subtype selective ligands, with unique pharmacological profiles, will allow researchers to elucidate the function of the individual subtypes within the cell.; We have explored many novel core scaffolds, heterocyclic and acyclic, in our search for subtype selective ligands. During our studies we discovered ligands containing new pharmacological profiles for estrogens. The pyrazolo[1,5-a]pyrimidine ligands provided us with two new pharmacological classes of ligands: (1) ERbeta potency selective antagonists and (2) ERbeta potency and efficacy selective antagonists. These ligands provide researchers with the ability to selectively antagonize ERbeta allowing for them to study the effects of ERbeta inhibition in cells, in the presence of ERalpha. Although these are interesting ligands we desired to develop an ERbeta potency selective agonist. An ERbeta selective agonist will allow researchers to study the role of ERbeta when activated. To aid in the development of ERbeta selective agonists we described a pharmacophore model that we believed would aid in ligand design. Using this model we developed a series of ERbeta potency and efficacy selective agonists. The new pharmacological profiles of estrogens that we have developed will provide researchers with additional tools to study and elucidate the role of the estrogen receptor.