Discovery of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

Bioorg Med Chem. 2015 Sep 1;23(17):5293-302. doi: 10.1016/j.bmc.2015.07.068. Epub 2015 Aug 1.

Abstract

A novel series of N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides as RORγt inverse agonists was discovered. Binding mode analysis of a RORγt partial agonist (2c) revealed by co-crystal structure in RORγt LBD suggests that the inverse agonists do not directly interfere with the interaction between H12 and the RORγt LBD. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 3m with a pIC50 of 8.0. Selected compounds in the series showed reasonable activity in Th17 cell differentiation assay as well as low intrinsic clearance in mouse liver microsomes.

Keywords: Crystal structure; RORγt inverse agonists; Th17 cell differentiation; Thiazole ether amides.

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacology*
  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Drug Inverse Agonism*
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Th17 Cells / cytology
  • Th17 Cells / drug effects*
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*

Substances

  • Amides
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Thiazoles