264130-01-0Relevant academic research and scientific papers
Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101)
Rew, Yosup,Du, Xiaohui,Eksterowicz, John,Zhou, Haiying,Jahchan, Nadine,Zhu, Liusheng,Yan, Xuelei,Kawai, Hiroyuki,McGee, Lawrence R.,Medina, Julio C.,Huang, Tom,Chen, Chelsea,Zavorotinskaya, Tatiana,Sutimantanapi, Dena,Waszczuk, Joanna,Jackson, Erica,Huang, Elizabeth,Ye, Qiuping,Fantin, Valeria R.,Sun, Daqing
, p. 7767 - 7784 (2018/09/06)
The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.
Synthesis of 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(3-methyl-1-butynyl)-4,9-estra dien-3-one and 11β-(4-acetophenyl)-17β-hydroxy-17α-(3-methyl-1-butynyl)-4,9-estradien-3-one: Two new analogs of mifepristone (RU-486)
Hazra, Braja G.,Basu, Sourav,Pore, Vandana S.,Joshi, Padmakar L.,Pal, Debnath,Chakrabarti, Pinak
, p. 157 - 162 (2007/10/03)
From the structure activity relationship, two new analogs, 2 and 3, of the potent progesterone antagonist mifepristone 1 have been designed. The syntheses of these two analogs have been achieved in eleven steps through modified synthetic sequences and improved procedures starting from (+)-estrone. In comparison with mifepristone 1, the relative binding affinities of compound 2 for the progesterone receptor was found to be more, whereas that of compound 3 was less. Copyright (C) 2000 Elsevier Science Inc.
