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

Selective agonism of the estrogen receptor (ER) subtypes, ER alpha and ER beta, 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 17 beta-estradiol geometry in the design of ER beta 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 ER beta selective structure-activity relationship. We report ER beta agonists with low nanomolar potency, greater than 200-fold selectivity for ER beta over ER alpha, 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 ER beta selective agonists measure favorably against clinically developed ER beta agonists and support further evaluation of carborane-based selective estrogen receptor modulators.