Discovery of 4-((2S,5R)-2-((difluoromethoxy)methyl)-5-(4-(trifluoromethyl)phenyl)piperidin-1-yl)-N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)benzamide as a potent, orally available RORγt inverse agonist.

RORγt, a member of the nuclear receptor family, plays a central role in directing Th17 cell differentiation and pro-inflammatory function. Dysregulation of this transcription factor contributes significantly to autoimmune conditions such as psoriasis, rheumatoid arthritis, and multiple sclerosis. Consequently, inhibition of RORγt has attracted considerable interest as a therapeutic approach for these disorders. In this study, we designed and synthesized a series of aryl sulfonyl derivatives as RORγt inhibitors. Selected compounds were functionally characterized as inverse agonists, with compound 7 as the initial lead. Through a scaffold-hopping strategy and systematic structure-activity relationship (SAR) studies of key substituents, we identified potent RORγt inhibitors with favorable oral bioavailability. Compound 8v emerged as the most promising candidate. In vivo pharmacokinetic studies demonstrated that 8v possessed good oral absorption. In addition, 8v showed moderate metabolic stability in human and mouse liver microsomes (t₁/₂ = 45 min and 151 min, respectively). Furthermore, in a mouse model of LPS-induced systemic inflammation-where IL-17 elevation is mediated by T-cell activation-and in an IMQ-induced psoriasis-like dermatitis model, 8v significantly inhibited IL-17 secretion and ameliorated disease-related symptoms. Collectively, these results support the therapeutic potential of small-molecule RORγt modulators for the treatment of inflammatory and autoimmune diseases.