Structure-Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists

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Abstract

Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para-carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para-carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.

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Sedlák, D., Wilson, T. A., Tjarks, W., Radomska, H. S., Wang, H., Kolla, J. N., … Coss, C. C. (2021). Structure-Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists. Journal of Medicinal Chemistry, 64(13), 9330–9353. https://doi.org/10.1021/acs.jmedchem.1c00555

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