Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors

Bioorg Med Chem. 2014 Jan 15;22(2):692-702. doi: 10.1016/j.bmc.2013.12.021. Epub 2013 Dec 21.

Abstract

Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.

Keywords: Multiple sclerosis; RORγt inhibitor; Rheumatoid arthritis; Th17 cell differentiation.

MeSH terms

  • Administration, Oral
  • Amides / administration & dosage
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Arthritis / chemically induced
  • Arthritis / drug therapy*
  • Cell Differentiation / drug effects
  • Collagen
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Humans
  • Mice
  • Molecular Structure
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Th17 Cells

Substances

  • Amides
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Collagen