Discovery of N-indanyl benzamides as potent RORγt inverse agonists.


State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, 1111 Zhongshan North No. 1 Road, Shanghai, 200437, China. Electronic address: [Email]


The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) 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 RORγt 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 RORγt 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 RORγt inverse agonists. Binding modes of the two enantiomers 5c and 5d in RORγt ligand binding domain were also discussed.


Autoimmune diseases,Binding modes,N-indanyl benzamides,RORγt inverse agonists,Th17 cells,