基于靶点黄嘌呤氧化酶的化合物CC18022抗高尿酸血症作用的研究

The anti-hyperuricemic effects of compound CC18022 targeting xanthine oxidase

高尿酸血症不仅作为痛风发病的生化基础,还与代谢综合征、心血管疾病、慢性肾病等疾病的发生发展密切相关。黄嘌呤氧化酶(xanthine oxidase,XOD)是体内尿酸生成的关键催化酶,也是抗高尿酸血症药物的重要靶点。本研究以XOD为靶点,设计合成化合物CC18022,经过分子对接分析观察到其与XOD具有较紧密的结合。体外实验发现CC18022可显著抑制XOD活性,半数抑制浓度达到纳摩尔数量级,与临床使用的XOD抑制剂非布索坦的体外XOD抑制程度相当。分别应用急性与慢性高尿酸血症小鼠模型检测,发现CC18022在体内具有显著降血尿酸作用,并呈良好的剂量依赖性。动物福利和实验过程均遵循中国医学科学院药物研究所动物伦理委员会的规定。结果显示CC18022可降低急性高尿酸血症小鼠的血清XOD活性,以及与嘌呤吸收、代谢相关的小肠组织、肝脏的XOD活性。因此,新结构类型化合物CC18022显示较强的XOD抑制活性和显著的抗高尿酸血症效果,具有良好的研发前景。

Hyperuricemia is not only the biochemical basis of gout,but also closely related to the development of metabolic syndrome,cardiovascular diseases,chronic kidney disease,etc.Xanthine oxidase(XOD)is the key catalytic enzyme for uric acid biosynthesis,therefore the vital target for anti-hyperuricemic drugs.In this study,compound CC18022 was designed and synthesized specifically targeting to XOD.Molecular docking analysis indicated a fairly tight binding between CC18022 and XOD.In the in vitro study,CC18022 significantly inhibited XOD activity with a half maximal inhibitory concentration(IC50)value in the order of nmol·L-1,which is relative to the XOD inhibitor febuxostat.By using both acute and chronic hyperuricemic mice model,compound CC18022 was found to have serum uric acid-lowering effect in a dose-dependent manner in vivo.The animal welfare and experimental processes were in accordance with the provisions of the Animal Ethics Committee of the Institute of Materia Medica,Chinese Academy of Medical Sciences.In the acute hyperuricemic mice,CC18022 significantly inhibited serum XOD activity,and also the XOD activity in intestine and liver,which were related to purine absorption and metabolism.Therefore,the novel compound CC18022 exhibited significant inhibition on XOD activity and anti-hyperuricemic effects,making it a favorable candidate for further research.