Structure-activity relationship-guided development of retinoic acid receptor-related orphan receptor gamma (RORγ)-selective inverse agonists with a phenanthridin-6(5H)-one skeleton from a liver X receptor ligand

Bioorg Med Chem. 2014 May 1;22(9):2799-808. doi: 10.1016/j.bmc.2014.03.007. Epub 2014 Mar 17.


Retinoic acid receptor-related orphan receptors (RORs), which belong to the nuclear receptor superfamily, regulate many physiological processes, including hepatic gluconeogenesis, lipid metabolism, immune function and circadian rhythm. Since RORs resemble liver X receptors (LXRs) in the fold structure of their ligand-binding domains, we speculated that ROR-mediated transcription might be modulated by LXR ligands, in line with the multi-template hypothesis. Therefore, we screened our LXR ligand library for compounds with ROR ligand activity and identified a novel ROR ligand with a phenanthridin-6(5H)-one skeleton. Structure-activity relationship studies aimed at separating ROR inverse agonistic activity from LXR-agonistic activity enabled us to develop a series of ROR inverse agonists based on the phenanthridin-6(5H)-one skeleton, including a RORγ-selective inverse agonist.

Keywords: Inverse agonist; LXR; Phenanthridinone; ROR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Inverse Agonism
  • HEK293 Cells
  • Humans
  • Ligands
  • Liver X Receptors
  • Orphan Nuclear Receptors / chemistry
  • Orphan Nuclear Receptors / metabolism
  • Phenanthrenes / chemical synthesis
  • Phenanthrenes / chemistry*
  • Phenanthrenes / metabolism
  • Protein Binding
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Receptors, Retinoic Acid / chemistry*
  • Receptors, Retinoic Acid / metabolism


  • Ligands
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Phenanthrenes
  • Protein Isoforms
  • Receptors, Retinoic Acid
  • retinoic acid receptor gamma
  • phenanthridone