发现治疗炎症性肠病的新型 Vanin-1 抑制剂噻唑羧酰胺类化合物

IF 6.8 1区 医学 Q1 CHEMISTRY, MEDICINAL
Tao Xie, Gao-Yao Cao, Shize Zhang, Meng-Ke Li, Xin Jin, Liu Liu, Guangji Wang, Le Zhen
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引用次数: 0

摘要

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希望的靶点。本研究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 细胞和组织水平上对 vanin-1 具有强效抑制作用,其与靶点的结合模式通过共晶体结构得到了证实。X17 在大鼠体内的生物利用度高达 81%,对血清 vanin-1 的抑制作用也呈浓度依赖性。在DSS诱导的小鼠结肠炎模型中,X17表现出了强大的抗炎和抗氧化活性,抑制了炎症因子的表达和髓过氧化物酶的活性,提高了结肠谷胱甘肽储备,恢复了肠道屏障。总之,这些研究发现了一种有效的 vanin-1 抑制剂,为进一步开发治疗 IBD 的候选药物提供了机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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.
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来源期刊
Journal of Medicinal Chemistry
Journal of Medicinal Chemistry 医学-医药化学
CiteScore
4.00
自引率
11.00%
发文量
804
审稿时长
1.9 months
期刊介绍: The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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