Development of novel silanol-based human pregnane X receptor (PXR) agonists with improved receptor selectivity

Bioorg Med Chem. 2018 Aug 15;26(15):4493-4501. doi: 10.1016/j.bmc.2018.07.038. Epub 2018 Jul 24.


Pregnane X receptor (PXR) is a ligand-dependent transcription factor that is considered to be a potential therapeutic target for multiple diseases. Herein, we report the development and structure-activity relationship studies of a new series of hPXR agonists. Focusing on our recently developed silanol-sulfonamide scaffold, we developed the potent hPXR agonist 28, which shows good selectivity over hLXRα and β, hFXR, and hRORα and γ. Examination of the structure-activity relationship suggested a possible strategy to manipulate the selectivity. Docking simulation indicated the presence of an additional binding cavity and polar contacts in the ligand-binding pocket of hPXR. This information should be helpful for the future development of more potent and selective hPXR ligands.

Keywords: Alcohol/silanol-exchange; C/Si-exchange; Nuclear receptor; Pregnane X receptor; Sila-substitution; Silanol; T0901317.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Design
  • Humans
  • Liver X Receptors / agonists
  • Liver X Receptors / metabolism
  • Molecular Docking Simulation
  • Orphan Nuclear Receptors / antagonists & inhibitors
  • Orphan Nuclear Receptors / metabolism
  • Pregnane X Receptor / agonists*
  • Pregnane X Receptor / metabolism
  • Protein Structure, Tertiary
  • Silanes / chemical synthesis
  • Silanes / chemistry*
  • Silanes / metabolism
  • Structure-Activity Relationship


  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Pregnane X Receptor
  • Silanes
  • silanol