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

J Med Chem. 2021 Jul 8;64(13):9330-9353. doi: 10.1021/acs.jmedchem.1c00555. Epub 2021 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boron Compounds / chemical synthesis
  • Boron Compounds / chemistry
  • Boron Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Estrogen Receptor beta / agonists*
  • Estrogens / chemical synthesis
  • Estrogens / chemistry
  • Estrogens / pharmacology*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship


  • Boron Compounds
  • Estrogen Receptor beta
  • Estrogens