Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists

J Med Chem. 2002 Jun 6;45(12):2417-24. doi: 10.1021/jm0105530.

Abstract

An approach to the computer-assisted, pharmacophore design of nonsteroidal templates for the glucocorticoid receptor (GR) that contained an element of pseudo-C2 symmetry was developed. The enatiomer of the initial design, 1Ra, and not the designed molecule, 1S, showed the desired ligand binding to the GR. The pseudo-C2 symmetry of the template allowed for rapid improvements in GR activity resulting in potent, selective, nonsteroidal GR antagonists, CP-394531 and CP-409069.

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Humans
  • Ligands
  • Models, Molecular
  • Phenanthrenes / chemical synthesis*
  • Phenanthrenes / chemistry
  • Phenanthrenes / pharmacology
  • Radioligand Assay
  • Receptors, Glucocorticoid / agonists
  • Receptors, Glucocorticoid / antagonists & inhibitors*
  • Receptors, Glucocorticoid / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transfection

Substances

  • 4a-benzyl-2-chloroethynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,7-diol
  • 4a-benzyl-2-prop-1-ynyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-2,7-diol
  • Ligands
  • Phenanthrenes
  • Receptors, Glucocorticoid