新型FABP4抑制剂的优化合成、构效关系及其抗II型糖尿病与动脉粥样硬化活性研究

Type II diabetes mellitus and atherosclerosis are deadly disease combination and severely affect the health of human beings. Recent studies indicated that fatty acid-binding protein 4 (FABP4/aP2) plays key role in the development of insulin resistance and inflammation, and has been potential and important drug target for the treatment of type 2 diabetes and atherosclerosis. In our previous study, pyrrolo[3,2-d]pyrimidine-2,4-dione derivative 8g exhibited appropriate inhibition of FABP4 activity (IC50: 4.09μM), inhibited the expression of gene and protein, and partially improved blood glucose level, reduced inflammatory atheromatous plaques in vivo. In this study, we will focus on these planned works as follow: To design novel small-molecule 8g analogues on the basis of previous study; To synthesize 8g-related analogues which first selected by virtual assessment of docking score, drug-likeness, pharmacokinetics and toxicity, and to finish inhibitory assay against FABP4 and further obtain drug hits; To summarize clear structure-activity relationship, and then to guide chemical modification based on hits’ structures and to explore drug lead; To evaluate lead's pharmacological activities in the two classical animal models of type II diabetes and atherosclerosis, as well as to accomplish studies of pharmacokinetics and toxicity. In summary, these researches are aim to achieve one potent and safe FABP4 inhibitor as drug candidate for the treatment of type II diabetes and atherosclerosis.

II型糖尿病与动脉粥样硬化是一对致命组合，严重危害人类健康。近年研究证实脂肪酸结合蛋白4（FABP4）在胰岛素抵抗与炎症过程中扮演重要角色，已成为治疗II型糖尿病和动脉粥样硬化潜在的药物靶标。前期研究中，根据靶点设计的吡咯并嘧啶酮衍生物8g能抑制FABP4的活性（IC50: 4.09μM）并下调细胞水平Fabp4基因和蛋白表达，改善体内血糖水平、减小动脉粥样硬化斑块。鉴于已取得良好开端，本项目拟针对活性分子8g结构做进一步优化并设计全新的类似物库；通过靶标对接、类药性、药代与毒理虚拟评估后，对优选目标分子进行化学合成与FABP4活性筛选，获得一定数量的苗头化合物；同时探讨构-效关系，于苗头化合物之上指导结构的定向修饰，发现先导化合物，进而完成其在II型糖尿病、动脉粥样硬化模型中药效学及药代和初步毒性评价，以期获得一个高效安全的候选分子，为FABP4抑制剂的研究与应用提供新的思路和重要依据。

基于先导化合物结构和文献调研，课题组经过结构设计、化学合成和活性筛选，发现结构新颖的FABP4抑制剂8g。FABP4抑制剂8g作为一种新型的FABP4抑制剂，可以有效的抑制脂肪细胞的分化及炎症反应，具有良好的调节脂质代谢紊乱疾病的体内效果，特别在动脉粥样硬化、饮食诱导肥胖和非酒精性脂肪肝模型中。其调节脂质代谢及炎症反应的作用通路与PPARγ、MAPK及NF-κB通路有密切地关联，其中，FABP4调控JNK及IKKβ的表达进而抑制NF-κB的转录活性，并且对IL-6发挥强抑制作用是8g发挥调控炎症反应的可能途径。在此基础上，课题组基于FABP4抑制剂8g结构以黄嘌呤等为母核，进行结构修饰与化学合成，获得34个全新结构的小分子化合物，其中新颖结构小分子化合物盐酸盐11c，其在DIO模型中展示抗肥胖效果。本课题研究成果对开发新的强有力的治疗动脉粥样硬化、肥胖和非酒精性脂肪肝药物具有重要的意义。除此，本课题组首次在小鼠缺血再灌注致肾损伤（I/R）模型中发现，FABP4基因和蛋白水平显明上调，并确证FABP4高表达于肾小管上皮细胞。课题组通过FABP4抑制剂BMS309403治疗的缺血再灌注致肾损伤的小鼠，肾脏组织病理损伤得到明显改善。通过TUNEL实验，BMS309403显著减少肾小管上皮细胞的凋亡，其作用机制可能是通过FABP4介导肾小管上皮细胞的内质网应激和炎症发挥作用。本课题研究已构建FABP4全身敲除小鼠，进一步机制探索工作正在进行中。.