Discovery of Thiazole Carboxamides as Novel Vanin‑1 Inhibitors for Inflammatory Bowel Disease Treatment

Inflammatory bowel disease (IBD) is a clinically heterogeneous
disease demanding more therapeutic targets and intervention strategies.
Vanin-1, an oxidative stress-regulating protein, has emerged as a
promising target for alleviating inflammation and oxidative stress.
In this study, a series of thiazole carboxamide derivatives as vanin-1
inhibitors were designed and synthesized. The preferred compound, X17, demonstrated potent inhibition against vanin-1 at the
protein, HT-29 cell, and tissue levels, whose binding mode with the
target was confirmed via the cocrystal structure. X17 achieved a high bioavailability of 81% in rats, accompanied by concentration-dependent
inhibition of serum vanin-1. In a DSS-induced mouse colitis model, X17 exhibited potent anti-inflammatory and antioxidant activities,
repressing the inflammatory factor expressions and myeloperoxidase
activity, elevating the colonic glutathione reserve, and restoring
the intestinal barrier. Collectively, these findings depict the discovery
of a potent vanin-1 inhibitor, providing an opportunity for further
drug candidate development for treating IBD.