American Chemical Society
jm1c00555_si_001.pdf (9.81 MB)

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

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journal contribution
posted on 2021-06-28, 19:16 authored by David Sedlák, Tyler A. Wilson, Werner Tjarks, Hanna S. Radomska, Hongyan Wang, Jayaprakash Narayana Kolla, Zbigniew J. Leśnikowski, Alena Špičáková, Tehane Ali, Keisuke Ishita, Liva Harinantenaina Rakotondraibe, Sandip Vibhute, Dasheng Wang, Pavel Anzenbacher, Chad Bennett, Petr Bartunek, Christopher C. Coss
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.