2. Academic Validation
  3. Structure-Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists

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.
David Sedlák 1,  Tyler A Wilson 2,  Werner Tjarks 3,  Hanna S Radomska 4,  Hongyan Wang 4,  Jayaprakash Narayana Kolla 1,  Zbigniew J Leśnikowski 5,  Alena Špičáková 6,  Tehane Ali 3,  Keisuke Ishita 3,  Liva Harinantenaina Rakotondraibe 3,  Sandip Vibhute 2,  Dasheng Wang 2,  Pavel Anzenbacher 6,  Chad Bennett 2 7,  Petr Bartunek 1,  Christopher C Coss 4 7
Affiliations

Affiliations

  • 1 CZ-OPENSCREEN, Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic.
  • 2 Medicinal Chemistry Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States.
  • 3 Division of Medicinal Chemistry and Pharmacognosy College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 4 Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
  • 5 Laboratory of Medicinal Chemistry, Institute of Medical Biology PAS, 106 Lodowa Street, 93-232 Lodz, Poland.
  • 6 Department of Pharmacology, Faculty of Medicine, Palacky University, Hněvotínská 3, 77515 Olomouc, Czech Republic.
  • 7 Drug Development Institute, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States.
PMID: 34181409 DOI: 10.1021/acs.jmedchem.1c00555
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.

Figures
Products