Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)

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...

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Published in:Journal of medicinal chemistry 2019-07, Vol.62 (14), p.6751-6764
Main Authors: Du, Xiaohui, Eksterowicz, John, Zhou, Haiying, Rew, Yosup, Zhu, Liusheng, Yan, Xuelei, Medina, Julio C, Huang, Tom, Chen, Xi, Sutimantanapi, Dena, Jahchan, Nadine, Kong, Wayne, Sun, Jessica, Zavorotinskaya, Tatiana, Ye, Qiuping, Fantin, Valeria R, Sun, Daqing
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cited_by cdi_FETCH-LOGICAL-a348t-e244a470573c816a6fe89db330adf81ccc7b5cacf8bb70d84a2e1f0219ca68fe3
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container_end_page 6764
container_issue 14
container_start_page 6751
container_title Journal of medicinal chemistry
container_volume 62
creator Du, Xiaohui
Eksterowicz, John
Zhou, Haiying
Rew, Yosup
Zhu, Liusheng
Yan, Xuelei
Medina, Julio C
Huang, Tom
Chen, Xi
Sutimantanapi, Dena
Jahchan, Nadine
Kong, Wayne
Sun, Jessica
Zavorotinskaya, Tatiana
Ye, Qiuping
Fantin, Valeria R
Sun, Daqing
description 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.
doi_str_mv 10.1021/acs.jmedchem.9b00711
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title Discovery of a Potent Steroidal Glucocorticoid Receptor Antagonist with Enhanced Selectivity against the Progesterone and Androgen Receptors (OP-3633)
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