Discovery of two novel (4-hydroxyphenyl) substituted polycyclic carbocycles as potent and selective estrogen receptor beta agonists

Abstract

Two (4-hydroxyphenyl) substituted polycyclic carbocycles were prepared and assayed for estrogen receptor activity. 4-(4-Hydroxyphenyl)tricyclo[3.3.1.13,7]decane-1-methanol (5a/b) and 7-(4-hydroxyphenyl)spiro[3.5]nonan-2-ol ((±)-11) were found to be potent ERβ agonists (1.9 ± 0.4 nM and 6.2 ± 1.4 nM respectively) in a cell-based functional assay. Furthermore, both 5a/b and 11 were highly selective for ERβ over ERα (377 and 1,100-fold selective respectively). While neither compound inhibited CYP2D6 or CYP3A4 at concentrations up to 62.5 μM, 5a/b did have weak binding to CYP2C9 with an IC50 of 10 ± 0.5 μM. Computational assessment of 5a/b and 11 predicted the most probable site of metabolism would be ortho to the phenolic hydroxyl group.