Synthesis and SAR study of novel pseudo-steroids as potent and selective progesterone receptor antagonists

Bioorg Med Chem Lett. 2009 Jul 15;19(14):3977-80. doi: 10.1016/j.bmcl.2009.01.095. Epub 2009 Jan 31.

Abstract

Synthesis of novel 7-pseudo-steroids 1c has been achieved from trenbolone 3 via an efficient 14 step sequence with overall yields of 10-15%. Various substitutions were incorporated at both the aromatic side chain as well as the D ring. The orientation of aromatic side chain at C10 plays a crucial role for progesterone receptor (PR) activity. Compound 2a (T47D=1nM) with -NMe(2) para to the aromatic group along with spirofurane groups in the D ring was the optimal substitution. All compounds were also evaluated for glucocorticoid receptor (GR) antagonist activities in vivo in a rat and found efficacious in uterine complement C3 assay via the oral route of administrations.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzoxepins / chemical synthesis*
  • Benzoxepins / chemistry
  • Benzoxepins / pharmacology
  • Computer Simulation
  • Crystallography, X-Ray
  • Female
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Progesterone / antagonists & inhibitors*
  • Receptors, Progesterone / metabolism
  • Structure-Activity Relationship
  • Trenbolone Acetate / chemistry

Substances

  • Benzoxepins
  • Receptors, Glucocorticoid
  • Receptors, Progesterone
  • Trenbolone Acetate