Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit <b>1</b>, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound <b>14d</b> stands out with IC₅₀ values of 0.110 μM for RORγt and of 0.297 μM for DHODH. With acceptable mouse pharmacokinetic profiles, <b>14d</b> exhibited remarkable <i>in vivo</i> anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.