AI Article Synopsis
- Scientists modified mifepristone to discover new derivatives that have better selectivity for certain receptors, focusing on progesterone (PR) and androgen (AR) receptors.
- Adding a methyl group to the C10 position of the steroid greatly affected its activity on these receptors, leading to the identification of OP-3633 as a strong glucocorticoid receptor (GR) antagonist.
- OP-3633 showed superior effects in blocking GR activity in a specific cancer model, making it a promising candidate for clinical trials aimed at overcoming or preventing therapy resistance.
Article Abstract
Structure-based modification of mifepristone () 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 () 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 . Furthermore, demonstrated substantial inhibition of GR transcriptional activity in the GR positive HCC1806 triple negative breast cancer xenograft model. Overall, compound is a promising GR antagonist candidate to clinically evaluate the impact of GR inhibition in reversal or prevention of therapy resistance.
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| http://dx.doi.org/10.1021/acs.jmedchem.9b00711 | DOI Listing |
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