Substituted phenyl as a steroid A-ring mimetic: providing agonist activity to a class of arylsulfonamide nonsteroidal glucocorticoid ligands

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6645-9. doi: 10.1016/j.bmcl.2013.10.047. Epub 2013 Oct 31.

Abstract

A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.

Keywords: Arylsulfonamide; Glucocorticoid receptor; Glucocorticoid receptor agonist; Glucocorticoids; Mineralocorticoid receptor; Nuclear hormone receptor; Progesterone receptor.

MeSH terms

  • Binding Sites
  • Glucocorticoids / chemistry
  • Hydrogen Bonding
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Receptors, Glucocorticoid / agonists*
  • Receptors, Glucocorticoid / metabolism
  • Steroids / chemistry*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*

Substances

  • Glucocorticoids
  • Ligands
  • Receptors, Glucocorticoid
  • Steroids
  • Sulfonamides