Structure–Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists
| Autor: | Petr Bartunek, Alena Špičáková, Christopher C. Coss, Tyler A. Wilson, Jayaprakash Narayana Kolla, Tehane Ali, Keisuke Ishita, Chad Bennett, Hongyan Wang, Zbigniew J. Leśnikowski, Werner Tjarks, Pavel Anzenbacher, Hanna S. Radomska, David Sedlák, Dasheng Wang, Liva Harinantenaina Rakotondraibe, Sandip Vibhute |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Structural similarity Chemistry Estrogen receptor Ligand (biochemistry) 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences Nuclear receptor Selective estrogen receptor modulator Drug Discovery Cancer research Molecular Medicine Carborane Structure–activity relationship Receptor 030304 developmental biology |
| Zdroj: | Journal of Medicinal Chemistry. 64:9330-9353 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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