7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists.
Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.
Zhang
Puwen
P
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. Zhangp@wyeth.com
Kern
Jeffrey C
JC
Terefenko
Eugene A
EA
Fensome
Andrew
A
Unwalla
Ray
R
Zhang
Zhiming
Z
Cohen
Jeffrey
J
Berrodin
Thomas J
TJ
Yudt
Matthew R
MR
Winneker
Richard C
RC
Wrobel
Jay
J
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006900:Hydroxylation; D008958:Models, Molecular; D015394:Molecular Structure; D010077:Oxazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D001552:Benzazepines; D010077:Oxazepines; D011980:Receptors, Progesterone; D000469:Alkaline Phosphatase