A reversed sulfonamide series of selective RORc inverse agonists

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5769-5776. doi: 10.1016/j.bmcl.2014.10.037. Epub 2014 Oct 25.

Abstract

The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.

Keywords: IL-17; Inflammation; RORc; RORγ; RORγt; X-ray structure.

Publication types

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

MeSH terms

  • Binding Sites
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Cytokines / biosynthesis
  • Drug Inverse Agonism
  • HEK293 Cells
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Molecular Dynamics Simulation
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / toxicity

Substances

  • Cytokines
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sulfonamides