Analogues of the Potent and Selective ERβ Agonist trans-4-(4-Hydroxyphenyl)cyclohexanemethanol: Synthesis and Evaluation

Activation of estrogen receptor-beta (ERβ) has potential benefits for vasomotor symptoms as well as memory consolidation in menopausal women. Ten 4-(4-substituted cyclohexyl)phenols were synthesized and evaluated as ERβ agonists in a TR-FRET ligand displacement assay. Four of the more potent compounds, all of which contained fluoroalkyl groups as the 4-substituent, were further assessed for agonist and antagonist activity in cell-based functional assays for ERβ and ERα. The 4-(4-fluoroalkyl-cyclohexyl)phenols were all >50-fold selective for ERβ over ERα, and none were found to be antagonists for either ERβ or ERα at 7,250 nM. Detection of 200 μM of trans-4-(4-(fluoromethyl)cyclohexyl)phenol in the presence of mouse brain homogenate was possible by 19F NMR spectroscopy.