Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists

Bioorg Med Chem. 2016 Mar 15;24(6):1384-91. doi: 10.1016/j.bmc.2016.02.014. Epub 2016 Feb 9.

Abstract

Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.

Keywords: Dibenzoxazepine; MR; MR antagonist; Mineralocorticoid receptor; Spirooxindole.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • Dibenzoxazepines / chemical synthesis
  • Dibenzoxazepines / chemistry
  • Dibenzoxazepines / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Mineralocorticoid Receptor Antagonists / chemical synthesis
  • Mineralocorticoid Receptor Antagonists / chemistry
  • Mineralocorticoid Receptor Antagonists / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Receptors, Mineralocorticoid / metabolism*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Dibenzoxazepines
  • Indoles
  • Mineralocorticoid Receptor Antagonists
  • Receptors, Mineralocorticoid
  • Spiro Compounds