Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ERα
Pepermans, R. A.; Tenorio, A. J.; Saxon, T.; Talipov, M. R.; Maio, W. A.; Ramesh, C.; Prossnitz, E. R.; Arterburn, J. B.
Show abstract
The classical estrogen receptor (ER) is a steroid hormone receptor known for its role in both health and disease. ER, like its counterpart ER{beta}, acts as a receptor for its endogenous ligand 17{beta}-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 ER and functional potencies in ER mediated assays. We identify a new substituted compound 9 that achieves subnanomolar potencies for ER binding (IC50= 0.45 nM) and ER dependent transcription (EC50= 0.37 nM) and proliferation (EC50= 0.03 nM), with potencies approaching those of E2. The high potency of 9 provides a promising scaffold for the potential development of new ER-targeted therapeutics.
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