Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORγ inhibitors using virtual screening, synthesis and biological evaluation

• RORγ is a promising drug target for treating Th17-mediated autoimmune diseases.
• A hit compound was obtained by structure-based virtual screening.
• 77 new compounds were designed and prepared starting from the hit compound.
• Several compounds acted as RORγ inhibitors and exhibited promising activities.
• SARs were analysed based on predicted binding modes and assessed activity.

Retinoic acid receptor-related orphan receptor γ (RORγ), a member of the nuclear hormone receptor superfamily, is a promising therapeutic target for treating Th17-mediated autoimmune diseases. We performed structure-based virtual screening targeting the RORγ ligand-binding domain. Among the tested compounds, s4 demonstrated RORγ antagonistic activities with micromolar IC50 values in both an AlphaScreen assay (20.27 μM) and a cell-based reporter gene assay (11.84 μM). Optimization of the s4 compound led to the identification of compounds 7j, 8c, 8k, and 8p, all of which displayed significantly enhanced RORγ inhibition with IC50 values of 40–140 nM. These results represent a promising starting point for developing potent small molecule RORγ inhibitors.

Benzo[cd]indol-2(1H)-one derivatives were developed as new RORγ inhibitors for developing therapeutic drug treating Th17 mediated autoimmune diseases.Figure optionsDownload as PowerPoint slide