Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ERα
- 1Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA
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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BibTeX
@misc{pepermans2026synthesis,
title = {{Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ERα}},
author = {R. A. Pepermans and A. J. Tenorio and T. Saxon and M. R. Talipov and W. A. Maio and C. Ramesh and E. R. Prossnitz and J. B. Arterburn},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754525},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754525v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ERα
AU - R. A. Pepermans
AU - A. J. Tenorio
AU - T. Saxon
AU - M. R. Talipov
AU - W. A. Maio
AU - C. Ramesh
AU - E. R. Prossnitz
AU - J. B. Arterburn
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754525
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754525v1
AB - 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.
ER -