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

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 1, a series of 2-aminotetrahydrobenzothiazoles
were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC50 values of 0.110 μM
for RORγt and of 0.297 μM for DHODH. With acceptable mouse
pharmacokinetic profiles, 14d exhibited remarkable in vivo 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.