Discovery of N-(6-Acetylpyridin-3-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide derivatives as a novel series of selective RORγt antagonists.

The retinoic acid receptor-related orphan receptor gamma t (RORγt) is a member of the nuclear receptor superfamily, expressed in lymphoid cells and driving Th17 cell differentiation and IL-17 production. The IL-17/IL-23 pathway is implicated in autoimmune and inflammatory diseases, such as inflammatory bowel disease (IBD). Targeting RORγt is considered a therapeutic intervention to suppress inflammation. Herein, we designed and synthesized a novel class of highly selective RORγt antagonists through scaffold-hopping and structure-activity relationship studies. Compound 14 (SPH7854) emerged as a preclinical candidate on the basis of its potent activity and favorable drug-like properties. SPH7854 demonstrated potent activity in preclinical models of inflammatory bowel disease and has advanced to clinical trials.