SAR studies of 6-aryl-1,3-dihydrobenzimidazol-2-ones as progesterone receptor antagonists

We have previously reported that the aryl substituted benzimidazolones, benzoxazinones, and oxindoles (e.g., 1–3) are progesterone receptor (PR) antagonists and have recently disclosed that the nature of 5- and 6-aryl moieties played a critical role in PR functional activity in the oxindole and benzoxazinone templates. For example, replacing the phenyl group of PR antagonists 2 and 3 with a 5′-cyanopyrrol-2′-yl moiety switched their functional activity to PR agonist activity (2a and 3a). These findings prompted us to examine if there is a similar effect of the 6-aryl moieties on the PR functional activity for the benzimidazolone template. Numerous analogs, such as 5, showed potent PR antagonist activity with about a 10-fold increase in potency as compared to those reported earlier in the same series. More interestingly, pyrrole-containing benzimidazolones 24–27 remained as PR antagonists in contrast to the PR agonist activity switch for oxindole and benzoxazinone scaffolds when a 5′-cyanopyrrol-2′-yl group was installed as a pendant aryl group.

Graphical abstract6-Aryl benzimidazol-2-ones showed progesterone receptor (PR) antagonist activity with a selection of aryl and R1 groups examined. Prudent choice of aryl and R1 groups led to potent PR antagonists in the T47D alkaline phosphatase assay.Figure optionsDownload full-size imageDownload as PowerPoint slide