Ring nitrogen-substituted non-steroidal estrogens: pyridine and pyrimidine analogs of the phenol in deoxyhexestrol experience resonance constraints on preferred ligand conformation

To develop compounds selective for estrogen receptor beta (ERβ), we substituted hydroxypyridine and pyrimidine heteroaryl groups for the characteristic phenol ring of non-steroidal estrogens. The unexpectedly low affinity showed by some of these compounds is ascribed, in part, to a resonance-enforced conformational constraint that prevents their optimal accommodation in the ER ligand binding pocket.