The nuclear receptor RORγt plays a key role in the differentiation and proliferation of T helper 17 (Th17) cells, which are associated with the production of IL-17 and other pro-inflammatory cytokines. Antibodies of IL-17, such as Secukinumab, are approved for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. Therefore, small molecule inverse agonists of RORγt may be useful to treat the autoimmune diseases related to the IL-17 pathway. Based on the RORγt binding mode of previously reported bicyclic sulfonamides from our team, a novel series of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines was designed, synthesized and evaluated as RORγt inverse agonists. Structure-activity relationship of this series, as well as the X-ray co-crystal structure of a compound-bound RORγt ligand binding domain, will be presented.

Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists

2019 Spring National Meeting

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