Structure-Based Design and Synthesis of Fluorene Derivatives as Novel RORt Inverse Agonists

A new series of fluorene derivatives was designed and synthesized as novel retinoic acid receptor-related orphan receptor gamma t (RORt) inverse agonists utilizing a molecular hybridization approach. The new compounds 10 - 15 were evaluated for their RORt activity using biochemical FRET and cellular reporter gene assays. Moreover, the inhibitory activity of the fluorene derivatives 10 - 15 in mouse Th17 cell differentiation assay was assessed. The hybrid compound 15 that combines both fluorene and arylsulfone moieties displayed promising RORt activity with IC50 values of 68.6 and 99.5 nm in FRET and cellular assays, respectively. In addition, molecular modeling studies were employed to investigate potential binding mode of 15 to RORt. These results render 15 a potential lead compound for development of therapeutics for Th17-driven autoimmune diseases.