Structure-Activity Relationship Studies of Trisubstituted Isoxazoles as Selective Allosteric Ligands for the Retinoic-Acid-Receptor-Related Orphan Receptor γt

J Med Chem. 2021 Jul 8;64(13):9238-9258. doi: 10.1021/acs.jmedchem.1c00475. Epub 2021 May 19.


The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain that provides an opportunity to overcome drawbacks associated with orthosteric modulators. Recently, trisubstituted isoxazoles were identified as a novel class of allosteric RORγt inverse agonists. This chemotype offers new opportunities for optimization into selective and efficacious allosteric drug-like molecules. Here, we explore the structure-activity relationship profile of the isoxazole series utilizing a combination of structure-based design, X-ray crystallography, and biochemical assays. The initial lead isoxazole (FM26) was optimized, resulting in compounds with a ∼10-fold increase in potency (low nM), significant cellular activity, promising pharmacokinetic properties, and a good selectivity profile over the peroxisome-proliferated-activated receptor γ and the farnesoid X receptor. We envisage that this work will serve as a platform for the accelerated development of isoxazoles and other novel chemotypes for the effective allosteric targeting of RORγt.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Structure-Activity Relationship


  • Isoxazoles
  • Ligands
  • Nuclear Receptor Subfamily 1, Group F, Member 3