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.
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.
Eugene A
EA
Terefenko
Jeffrey
J
Kern
Andrew
A
Fensome
Jay
J
Wrobel
Yuan
Y
Zhu
Jeffrey
J
Cohen
Richard
R
Winneker
Zhiming
Z
Zhang
Puwen
P
Zhang
D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D048588:Benzoxazines; D006727:Hormone Antagonists; D007211:Indoles; D011758:Pyrroles; D011980:Receptors, Progesterone