Design and synthesis of nonsteroidal progesterone receptor antagonists based on C,C'-diphenylcarborane scaffold as a hydrophobic pharmacophore

Eur J Med Chem. 2014 Sep 12:84:264-77. doi: 10.1016/j.ejmech.2014.07.034. Epub 2014 Jul 10.

Abstract

The progesterone receptor (PR) plays important roles in multiple physiological processes, including female reproduction. Here, we report the synthesis of nonsteroidal PR antagonists containing a boron cluster as the hydrophobic core. We found that 1,7-diphenyl-meta-carborane was the preferred substructure among the three carborane isomers. Compound 39 was the most potent PR antagonist (IC50: 29 nM). Compound 41 also exhibited potent activity (IC50: 93 nM), and did not bind to androgen receptor, glucocorticoid receptor or mineralocorticoid receptor. These compounds may be useful for investigating potential clinical applications of PR modulators.

Keywords: Carborane; Hydrophobic pharmacophore; Progesterone receptor (PR); Scaffold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemical synthesis
  • Acetanilides / chemistry*
  • Acetanilides / pharmacology*
  • Boron Compounds / chemical synthesis
  • Boron Compounds / chemistry*
  • Boron Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Structure
  • Receptors, Progesterone / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • 1-(4-cyanophenyl)-7-(4-(N-methylacetamido)phenyl))-1,7-dicarba-closo-dodecaborane
  • Acetanilides
  • Boron Compounds
  • Receptors, Progesterone