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.

中文翻译：

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发现噻唑羧酰胺作为新型 Vanin-1 抑制剂治疗炎症性肠病


炎症性肠病 （IBD） 是一种临床异质性疾病，需要更多的治疗靶点和干预策略。Vanin-1 是一种氧化应激调节蛋白，已成为缓解炎症和氧化应激的有前途的靶标。在本研究中，设计并合成了一系列噻唑羧酰胺衍生物作为 vanin-1 抑制剂。首选化合物 X17 在蛋白质、HT-29 细胞和组织水平上表现出对 vanin-1 的有效抑制，其与靶标的结合模式通过共晶结构得到证实。X17 在大鼠中实现了 81% 的高生物利用度，并伴有血清 vanin-1 的浓度依赖性抑制。在 DSS 诱导的小鼠结肠炎模型中，X17 表现出强大的抗炎和抗氧化活性，抑制炎症因子表达和髓过氧化物酶活性，提高结肠谷胱甘肽储备，恢复肠道屏障。总的来说，这些发现描述了一种强效 vanin-1 抑制剂的发现，为进一步开发治疗 IBD 的候选药物提供了机会。