Discovery of N-indanyl benzamides as potent RORγt inverse agonists

The retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) is a promising therapeutic target for treatment of Th17 cell-mediated autoimmune diseases. Based on a scaffold hopping/conformational restriction strategy, a series of N-indanyl benzamides as novel ROR gamma t inverse agonists was discovered. Exploration of structure-activity relationship on the piperazine ring, benzoyl moiety and cyclopentyl moiety of N-indanyl benzamides 2a and 2d led to identification of potent ROR gamma t inverse agonists. Compound 5c with (S)-enantiomer was found having an IC50 of 153.7 nM in Fluorescence Resonance Energy Transfer (FRET) assay, and an IC50 of 47.1 nM in mouse Th17 cell differentiation assay, which represents a promising starting point for developing potent small molecule ROR gamma t inverse agonists. Binding modes of the two enantiomers 5c and 5d in ROR gamma t ligand binding domain were also discussed. (C) 2019 Published by Elsevier Masson SAS.