Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists

Bioorg Med Chem Lett. 2015 Aug 1;25(15):2907-12. doi: 10.1016/j.bmcl.2015.05.055. Epub 2015 May 28.

Abstract

The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.

Keywords: GNE-0946; GNE-6468; IL-17; PPARγ; RORc; RORγ.

MeSH terms

  • Animals
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Cell Line
  • Cells, Cultured
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology*
  • Interleukin-17 / immunology
  • Liver / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • IL17A protein, human
  • Imidazoles
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Pyridines
  • Pyrimidines