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. Epub 2008 May 10.

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.

MeSH terms

  • Alkaline Phosphatase / antagonists & inhibitors
  • Alkaline Phosphatase / metabolism
  • Animals
  • Benzazepines / chemical synthesis*
  • Benzazepines / chemistry
  • Benzazepines / pharmacology*
  • Binding Sites
  • COS Cells
  • Chlorocebus aethiops
  • Female
  • Hydroxylation
  • Models, Molecular
  • Molecular Structure
  • Oxazepines / chemical synthesis*
  • Oxazepines / chemistry
  • Oxazepines / pharmacology*
  • Receptors, Progesterone / antagonists & inhibitors*
  • Receptors, Progesterone / metabolism
  • Structure-Activity Relationship

Substances

  • Benzazepines
  • Oxazepines
  • Receptors, Progesterone
  • Alkaline Phosphatase