Novel 6-aryl-1,4-dihydrobenzo[d]oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists.
The functional activity of 6-aryl benzoxazinone-based progesterone (PR) antagonists changed to PR agonism when the 2-carbonyl group was replaced by a 2-thiocarbonyl moiety. Based on this finding novel 6-aryl benzoxazine-2-thiones were synthesized and evaluated as PR agonists in various in vitro and in vivo assays. Several analogues had sub-nanomolar in vitro potency and showed excellent oral activities in rats. Compounds 15 and 29 had similar potencies to medroxyprogesterone acetate (MPA) in the in vitro T47D alkaline phosphatase assay and in vivo rat decidualization model. In contrast to MPA, 29 was highly selective (>500-fold) for PR over glucocorticoid and androgen receptors.
Zhang
Puwen
P
Chemical Sciences, Wyeth Research, Collegeville, PA 19426, USA. zhangp@wyeth.com
Terefenko
Eugene A
EA
Fensome
Andrew
A
Wrobel
Jay
J
Winneker
Richard
R
Zhang
Zhiming
Z
D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology; D003429:Cross Reactions; D003656:Decidua / Q000187:drug effects / Q000201:enzymology; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D010052:Ovariectomy; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011944:Receptors, Androgen / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D011980:Receptors, Progesterone / Q000819:agonists*; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000494:pharmacology*
D010078:Oxazines; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D013871:Thiones; D017258:Medroxyprogesterone Acetate; D000469:Alkaline Phosphatase