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

Chen JA, Ma H, Liu Z, Tian J, Lu S, Fang W, Ze S, Lu W, Xie Q, Huang J, Wang Y. Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor ?-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease. Journal of medicinal chemistry. 2022 Jan 13; 65(1):592-615.

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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 ?-t (ROR?t) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual ROR?t/DHODH inhibitors are expected not only to reduce ROR?t-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 , a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual ROR?t/DHODH inhibitors. Compound stands out with IC values of 0.110 µM for ROR?t and of 0.297 µM for DHODH. With acceptable mouse pharmacokinetic profiles, exhibited remarkable 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.





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