Discovery of a potent orally bioavailable retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) inhibitor, S18-000003.

Abstract The retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is the master transcription factor responsible for regulating the development and function of T -helper 17 (Th17) cells, which are related to the pathology of several autoimmune disorders. Therefore, ROR γ t is an attractive drug target for such Th17-mediated autoimmune diseases. A structure-activity relationship (SAR) study of lead compound 1 yielded a novel series of ROR γ t inhibitors, represented by compound 6 . Detailed SAR optimization, informed by X-ray cocrystal structure analysis, led to the discovery of a potent orally bioavailable ROR γ t inhibitor 25 , which inhibited IL-17 production in the skin of IL-23-treated mice by oral administration.