Discovery of carbazole carboxamides as novel RORγt inverse agonists

Abstract

A novel series of carbazole carboxamides was discovered as potent RORγt inverse agonists using a scaffold hybridization strategy. Structure-activity relationship exploration on the amide linker, carbazole ring and arylsulfone moiety of the hybrid amide 3a led to identification of potent RORγt inverse agonists. Compound 6c was found to have a good RORγt activity with an IC₅₀ of 58.5 nM in FRET assay, and reasonable inhibitory activity in mouse Th17 cell differentiation assay (58.8% inhibition at 0.3 μM). The binding mode of carbazole carboxamides in RORγt ligand binding domain was discussed.

Keywords: Autoimmune diseases; Binding mode; Carbazole carboxamides; RORγt inverse agonists; Th17 cells.