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.

CZ OPENSCREEN Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 142 20 Prague Czech Republic

Department of Pharmacology Faculty of Medicine Palacky University Hněvotínská 3 77515 Olomouc Czech Republic

Division of Medicinal Chemistry and Pharmacognosy College of Pharmacy The Ohio State University Columbus Ohio 43210 United States

Division of Pharmaceutics and Pharmacology College of Pharmacy The Ohio State University Columbus Ohio 43210 United States

Drug Development Institute Comprehensive Cancer Center The Ohio State University Columbus Ohio 43210 United States

Laboratory of Medicinal Chemistry Institute of Medical Biology PAS 106 Lodowa Street 93 232 Lodz Poland

Medicinal Chemistry Shared Resource Comprehensive Cancer Center The Ohio State University Columbus Ohio 43210 United States

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