A New Series of Estrogen Receptor Modulators That Display Selectivity for Estrogen Receptor β
| Autor: | Dana R Hohman, Lisa A. Orband-Miller, Susan L. Weaver, Eugene L. Stewart, Shawn P. Williams, John T. Moore, Thomas G. Consler, Paul Kenneth Spearing, Ning Go, Philip Stewart Turnbull, Millard H. Lambert, Ron L. Hale, Linda B. Moore, Stacey A. Jones, Amy T. Lu, Brad R. Henke, G. Bruce Wisely, Jean Shearin, R. Graham Robinett |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular endocrine system Transcription Genetic Estrogen receptor Crystallography X-Ray Ligands Partial agonist Radioligand Assay Structure-Activity Relationship Genes Reporter Drug Discovery Tumor Cells Cultured polycyclic compounds Estrogen Receptor beta Humans Structure–activity relationship Receptor reproductive and urinary physiology Estrogen receptor beta Triazines Chemistry Ligand binding assay Estrogen Receptor alpha Stereoisomerism Antiestrogen Receptors Estrogen Biochemistry Molecular Medicine Estrogen receptor alpha hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 45:5492-5505 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm020291h |
| Popis: | A series of 1,3,5-triazine-based estrogen receptor (ER) modulators that are modestly selective for the ERbeta subtype are reported. Compound 1, which displayed modest potency and selectivity for ERbeta vs ERalpha, was identified via high-throughput screening utilizing an ERbeta SPA-based binding assay. Subsequent analogue preparation resulted in the identification of compounds such as 21 and 43 that display 25- to 30-fold selectivity for ERbeta with potencies in the 10-30 nM range. These compounds profile as full antagonists at ERbeta and weak partial agonists at ERalpha in a cell-based reporter gene assay. In addition, the X-ray crystal structure of compound 15 complexed with the ligand binding domain of ERbeta has been solved and was utilized in the design of more conformationally restrained analogues such as 31 in an attempt to increase selectivity for the ERbeta subtype. |
| Databáze: | OpenAIRE |
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