Indazole estrogens: Highly selective ligands for the estrogen receptor β

The estrogen receptors, ERα and ERβ, are important pharmaceutical targets. To develop ERβ-selective ligands, we synthesized a series of nonsteroidal compounds having a phenyl-2H-indazole core with different groups at C-3. Several of these show high affinity and good ERβ selectivity, especially those with polar and/or polarizable substituents at this site (halogen, CF₃, nitrile); the best compounds have affinities for ERβ comparable to estradiol, with ERβ affinity selectivity >100. This potency and ERβ selectivity is also seen in cell-based transcriptional assays, where several compounds showed ERβ efficacies equivalent to that of estradiol with ERβ potency selectivities of 100. These compounds might prove useful as selective pharmacological probes to study the biological actions of estrogens mediated through ERβ, and they might lead to the development of useful pharmaceuticals. These findings also contribute to an evolving pharmacophore that characterizes certain nonsteroidal ligands having high ERβ subtype affinity and potency selectivity.