Identification of Novel RORγt Inverse Agonist YW-089 as a Preclinical Candidate for the Treatment of Autoimmune Diseases

Retinoic acid receptor-related orphan receptor γt (RORγt) is a key regulator of IL-17-producing T helper 17 (Th17) cell differentiation and an attractive target for autoimmune diseases. Although RORγt inverse agonists have shown clinical promise, identifying candidates with both high potency and favorable drug-like properties remain challenging. We previously reported the carboxyl-containing biaryl urea compound 3i, which reduced psoriasis severity in mice but exhibited poor microsomal stability and suboptimal pharmacokinetics (38% oral bioavailability in mice). Herein, optimization of sulfone-containing biaryl ureas led to the discovery of compound 4 (YW-089), a potent and selective RORγt inverse agonist (RORγ FRET IC50 = 27 nM; mTh17 IC50 = 140 nM). YW-089 demonstrated markedly improved metabolic stability across species (t1/2 > 145 min), favorable pharmacokinetics in mice, rats, and dogs (oral bioavailability 66%, 65%, and 73%, respectively), and robust efficacy in imiquimod- and IL-23-induced psoriasis mouse models, supporting its further preclinical development for autoimmune diseases.