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. 2018 Jun 23;9(7):641-645.
doi: 10.1021/acsmedchemlett.8b00058. eCollection 2018 Jul 12.

Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a Phenanthridinone Skeleton

Yuko Nishiyama  1 , Shuichi Mori  2 , Makoto Makishima  3 , Shinya Fujii  1 , Hiroyuki Kagechika  2 , Yuichi Hashimoto  1 , Minoru Ishikawa  1
Affiliations

Novel Nonsteroidal Progesterone Receptor (PR) Antagonists with a Phenanthridinone Skeleton

Yuko Nishiyama et al. ACS Med Chem Lett. .

Abstract

The progesterone receptor (PR) plays an important role in various physiological systems, including female reproduction and the central nervous system, and PR antagonists are thought to be effective not only as contraceptive agents and abortifacients but also in the treatment of various diseases, including hormone-dependent cancers and endometriosis. Here, we identified phenanthridin-6(5H)-one derivatives as a new class of PR antagonists and investigated their structure-activity relationships. Among the synthesized compounds, 37, 40, and 46 exhibited very potent PR antagonistic activity with high selectivity for PR over other nuclear receptors. These compounds are structurally distinct from other nonsteroidal PR antagonists, including cyanoaryl derivatives, and should be useful for further studies of the clinical utility of PR antagonists.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of PR agonists 1–2 and antagonists 3–10.
Scheme 1
Scheme 1. Synthesis of the Novel Analogs 32–40
Reagents and conditions: (a) CF3COCF3·1.5H2O, p-TsOH·H2O, toluene, reflux, 8–49%; (b) 2-iodobenzoic acids or 2-bromobenzoic acids, EDC, DMAP, DMF, 100 °C, 19–91%; (c) SEMCl, NaH, DMF, 0 °C to rt; (d) Pd(OAc)2, PCy3·HBF4, Cs2CO3, DMA, 130 °C, 9–44% in 2 steps; (e) TBAF, THF, reflux, 30–80%.
Figure 2
Figure 2
Western blot analysis of β1-Na/K-ATPase in T47D cells in the presence of test compounds.
See this image and copyright information in PMC

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