Development of N-(4-Phenoxyphenyl)benzenesulfonamide Derivatives as Novel Nonsteroidal Progesterone Receptor Antagonists

Abstract

ABSTRACT:We report here development of N-(4-phenoxyphenyl)benzenesulfonamide derivatives as a novel class of nonsteroidal progesterone receptor (PR) antagonists. PR plays key roles in various physiological systems, including the female reproductive system, and PR antagonists are candidates for clinical treatment of multiple diseases, including uterine leiomyoma, endometriosis, breast cancer, and some psychiatric disorders. We found that the benzenesulfonanilide skeleton functions as a novel scaffold for PR antagonists, and we adopted 3-chlorobenzenesulfonyl derivative 20a as a lead compound for structural development. Among the synthesized compounds, 3-trifluoromethyl derivative 32 exhibited the most potent PR-antagonistic activity, with high binding affinity for PR and selectivity over androgen receptor (AR). It is structurally distinct from other nonsteroidal PR antagonists, including cyanopyrrole derivatives, and further modification is expected to afford novel selective PR modulators.

Development of Boron-Cluster-Based Progesterone Receptor Antagonists Bearing a Pentafluorosulfanyl (SF₅) Group

“…13) However, all PR ligands in clinical use, including 2, possess a steroidal structure, which may cause significant adverse effects due to cross-activity with other steroid hormone receptors. 14) To avoid these adverse effects, several non-steroidal PR ligands have been developed, such as tanaproget (3) 15) and sulfonamide derivative 4 16) (Fig. 1).…”

“…In the case of 3, X-ray crystallographic analysis of the complex of 3 with the PR-LBD revealed that the cyano group of 3 interacts with Gln725 and Arg766 of PR-LBD, which are the same amino acid residues that interact with the 3-carbonyl group of 1. 15) In the previous study, we developed non-steroidal PR antagonists bearing a boron-cluster carborane as the hydrophobic core structure. [17][18][19][20] Carboranes, or more precisely dicarbacloso-dodecaboranes (C 2 B 10 H 12 ), are carbon-containing boron clusters with an icosahedral cage structure, and there are three isomers, depending on the positions of the two carbon atoms, that is, ortho-, meta-, and para-carborane.…”

Design, Synthesis and Biological Evaluation of Novel Nonsteroidal Progesterone Receptor Antagonists Based on Phenylamino-1,3,5-triazine Scaffold

“…[17][18][19] In addition to these tanaproget derivatives, nonsteroidal PR antagonists with novel chemotypes distinct from tanaproget (2) have been also investigated. For example, 3-aryl indole derivatives including 6 were developed as PR antagonists to treat uterine fibroids, 20) and other structures such as 7 and 8 have also been reported in recent years [21][22][23][24] (Fig. 1).…”

Novel Non-steroidal Progesterone Receptor Ligands Based on <i>m</i>-Carborane Containing a Secondary Alcohol: Effect of Chirality on Ligand Activity

“…15,16) However, all PR ligands currently in clinical use, including 2, are steroid derivatives, and may have significant adverse effects because of their cross-activity toward other steroid hormone receptors. 17) In order to avoid these adverse effects, non-steroidal PR ligands are required, and indeed, several non-steroidal ligands have been developed, such as tanaproget (3) 18) and a sulfonamide derivative (4) 19) (Fig. 1).…”