3-（萘-1-甲基取代）吡啶衍生物通过影响肠-肝-肾尿酸转运体GLUT9和URAT1降尿酸作用的分子机制

90%的高尿酸血症与尿酸排泄减少有关。人体内尿酸的排泄主要与肾脏和肠道尿酸转运体URAT1、GLUT9和ABCG2功能有关，靶向尿酸转运体的药物是近年来降尿酸药物研究的热点。本课题根据前期研究发现的URAT1尿酸转运的“柔性理论”设计合成了一类新的3-（萘-1-甲基取代）吡啶衍生物（如CDER167），体内外通过抑制URAT1和GLUT9活性发挥强大的降尿酸作用，其作用机制与肾脏、肠道和肝脏尿酸转运活性有关。本课题通过构建过表达或敲低URAT1、GLUT9和ABCG2体外细胞模型、三维模建及位点突变、高尿酸血症小鼠模型、URAT1或GLUT9基因敲除小鼠模型等研究该类化合物对URAT1和GLUT9的作用位点及其对肠、肝、肾中尿酸转运体的作用方式，阐明其作用的分子机制，不仅对开发具有自主知识产权的降尿酸新药具有迫切的应用价值，而且，对进一步设计和开发新的促尿酸排泄药有重要的指导意义。

More than 90% of the patients with primary hyperuricemia are associated with reduced uric acid excretion. However, urate transporters expressed in the kidney and intestinal play critical roles in the process of urate excretion, such as URAT1, GLUT9 and ABCG2. Therefore, discovery of the urate-lowering agents targeting those transporters have become novel strategies for hyperuricemia therapy. In this study, we designed and synthesized a series of 3-(naphthalene-1-methyl) pyridine derivatives (CDER167) based on the theory of flexibility we raised in our previous study. Evidences from our previous studies indicated that CDER167 was a potent inhibitor of both URAT1 and GLUT9 in vitro. Besides, it was proved to exert urate-lowering effects in mice with the hyperuricemia, which is associated with its effects on the urate transporters expressed in the kidney, intestinal and liver. To further evaluate and clarify the molecular mechanisms of CDER167, cell models over-expressing or SiRNA-transfection with URAT1, GLUT9, ABCG2 in combination with the construction of site mutants based on the homology models in silico were used to investigate the binding sites of CDER167 with URAT1, GLUT9 as well as ABCG2. We also aimed to use the hyperuricemic mice and URAT1 and GLUT9 knockout mice to illuminate the exact effects of CDER167 on the three transporters mentioned above. All these results could not only contribute to great values to the development of new uric acid-lowering drugs with independent intellectual property rights, but also open the market for discovering dual inhibitors of URAT1 and GLUT9 in China. Furthermore, our study could provide significant references for further designing and developing novel uricosuric agents.