Discovery of carbazole carboxamides as novel RORγt inverse agonists

A novel series of carbazole carboxamides was discovered as potent ROR gamma t 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 ROR gamma t inverse agonists. Compound 6c was found to have a good ROR gamma t 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 mu M). The binding mode of carbazole carboxamides in ROR gamma t ligand binding domain was discussed. (C) 2018 Elsevier Masson SAS. All rights reserved.