Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)
| Autor: | Xi Chen, John Eksterowicz, Jessica Sun, Tatiana Zavorotinskaya, Valeria R. Fantin, Xuelei Yan, Wayne Kong, Dena Sutimantanapi, Yosup Rew, Xiaohui Du, Haiying Zhou, Liusheng Zhu, Daqing Sun, Tom Huang, Qiuping Ye, Julio C. Medina, Nadine Jahchan |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Pharmacology 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Receptors Glucocorticoid Glucocorticoid receptor Drug Discovery Progesterone receptor Androgen Receptor Antagonists medicine Humans Receptor Triple-negative breast cancer 030304 developmental biology 0303 health sciences Chemistry Antiglucocorticoid Antagonist Mifepristone 0104 chemical sciences Androgen receptor 010404 medicinal & biomolecular chemistry Receptors Androgen Molecular Medicine Receptors Progesterone medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 62:6751-6764 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b00711 |
| Popis: | Structure-based modification of mifepristone (1) led to the discovery of novel mifepristone derivatives with improved selectivity profile. Addition of a methyl group at the C10 position of the steroid has a significant impact on progesterone receptor (PR) and androgen receptor (AR) activity. Within this series, OP-3633 (15) emerged as a glucocorticoid receptor (GR) antagonist with increased selectivity against PR and AR, improved cytochrome P450 inhibition profile, and significantly improved pharmacokinetic properties compared to 1. Furthermore, 15 demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound 15 is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance. |
| Databáze: | OpenAIRE |
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