Discovery of biaryls as RORγ inverse agonists by using structure-based design

Bioorg Med Chem Lett. 2016 May 15;26(10):2459-2463. doi: 10.1016/j.bmcl.2016.03.109. Epub 2016 Apr 1.

Abstract

RORγ plays a critical role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including T cells, γδ T cells, and innate lymphoid cells. RORγ-mediated inflammation has been linked to susceptibility to Crohn's disease, arthritis, and psoriasis. Thus inverse agonists of RORγ have the potential of modulating inflammation. Our goal was to optimize two RORγ inverse agonists: T0901317 from literature and 1 that we obtained from internal screening. We used information from internal X-ray structures to design two libraries that led to a new biaryl series.

Keywords: Biaryls; RORγ; Retinoid-related orphan receptor gamma; Sulfonamides; Tetrahydroquinolines.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Hydrocarbons, Fluorinated / chemistry*
  • Hydrocarbons, Fluorinated / pharmacology
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / chemistry
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Structure-Activity Relationship*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Hydrocarbons, Fluorinated
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sulfonamides
  • T0901317