6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin- 2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists.
Novel 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones were synthesized and tested as progesterone receptor (PR) antagonists. These compounds were potent and showed good selectivity for PR over other steroid receptors such as the glucocorticoid and androgen receptors (e.g., greater than 80-fold selectivity at PR for 4h). Numerous 6-aryl benzoxazinones (e.g., 4h-j) were active orally in the uterine decidualization and component C3 assays in the rats. In these in vivo models,4h had potencies comparable to mifepristone.
Zhang
Puwen
P
Chemical Sciences, Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. Zhangp@wyeth.com
Terefenko
Eugene A
EA
Fensome
Andrew
A
Wrobel
Jay
J
Winneker
Richard
R
Lundeen
Scott
S
Marschke
Keith B
KB
Zhang
Zhiming
Z
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D003656:Decidua / Q000187:drug effects; D005260:Female; D006727:Hormone Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D015735:Mifepristone / Q000494:pharmacology; D010052:Ovariectomy; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D006727:Hormone Antagonists; D010078:Oxazines; D011980:Receptors, Progesterone; D015735:Mifepristone; D008156:Luciferases; D000469:Alkaline Phosphatase