Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ERα

Abstract The classical estrogen receptor α (ERα) is a steroid hormone receptor known for its role in both health and disease. ERα, like its counterpart ERβ, acts as a receptor for its endogenous ligand 17β-estradiol (E2) and is capable of binding a diverse set of natural and synthetic small molecules. Several screening campaigns have identified various ER ligands, based on the oxabicyclo[3.3.1]-nonene scaffold, that act as ER agonists. One such campaign extensively characterized an oxabicyclic ER agonist, termed AB-1. Herein, we report the synthesis of a series of analogs based on the scaffold of AB-1 (herein termed 1 ), focusing on the enhancement of their binding to ERα and functional potencies in ER-mediated assays. We identify a new substituted compound 9 that achieves subnanomolar potencies for ERα binding (IC 50 = 0.45 nM) and ER-dependent transcription (EC 50 = 0.37 nM) and proliferation (EC 50 = 0.03 nM), with potencies approaching those of E2 . The high potency of 9 provides a promising scaffold for the potential development of new ERα-targeted therapeutics.