7-aryl 1,5-dihydro-benzo[e][1,4]oxazepin-2-ones and analogs as non-steroidal progesterone receptor antagonists

  • Bioorg Med Chem. 2008 Jul 1;16(13):6589-600. doi: 10.1016/j.bmc.2008.05.018.
Puwen Zhang  1 ,  Jeffrey C Kern ,  Eugene A Terefenko ,  Andrew Fensome ,  Ray Unwalla ,  Zhiming Zhang ,  Jeffrey Cohen ,  Thomas J Berrodin ,  Matthew R Yudt ,  Richard C Winneker ,  Jay Wrobel
Affiliations
  • 1. Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. [email protected]
PMID: 18504132 DOI: 10.1016/j.bmc.2008.05.018
Abstract

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.