吡唑并吡啶酮类腺苷酸活化蛋白激酶激活剂的构效关系及作用机制研究

As the most serious complication of a variety of diseases, such as obesity, hypertension, diabetes, infections, etc), chronic kidney disease (CKD) has become a serious hazard to human life. The morbidity and mortality of CKD have been rising increasing in recent years. However, there is no effective therapeutic agents in clinic. Currently, it has been reported that the activity of AMP-activated protein kinase (AMPK), as serine kinase, is inhibited at high energy state, causing abnormaility of two important markers of NF-κB (inflammation) and TGF-β (fibrosis), which result in persistent renal inflammation and fibrosis and eventually lead to end-stage renal failure. Therefore, AMPK has become an important target for anti-CKD drug discovery. We hypothesized that AMPK activators can improve the pathological status of CKD through regulating NF-κB and TGF-β simultaneously. Our previous studies showed that compound JXD-002, a 6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine derivative bound to the same allosteric site of AMPK enzyme as A-769662, an AMPK activators and bioisostere of JXD-002. In addition, JXD-002 displayed better AMPK activation and anti-fibrosis activity. In this study, crystal structure of AMPK complexed with A-769662 will be applied as a template and JXD-002 as the lead compound. Structure-based drug design, structure-activity relationships, mechanism of action and drug discovery research will be carried out to make innovative achievements in the basic research of AMPK activators with oxo-dihydro-1H-pyrazolo[3,4-b]pyridine scaffold and to discover more potent drug candidates with better druggability for the treatment of chronic kidney disease.

慢性肾病（CKD）已成为严重危害人类生命的多种疾病最严重的并发症，临床上缺乏有效的治疗药物。目前认为，在高能量状态下，腺苷酸活化蛋白激酶（AMPK）活性被抑制，引起两种重要标记物NF-κB（炎症）和TGF-β（纤维化）活性异常，引发肾脏持续的炎症及纤维化，最终导致终末期肾衰。因此，AMPK成为CKD药物研发的重要靶点。我们的假设是：AMPK激活剂可以通过同时调节NF-κB和TGF-β改善CKD的病理状态。前期研究表明，吡唑并吡啶酮类化合物JXD-002与互为电子等排体的AMPK激活剂A-769662结合模式一致，具有较好的激活AMPK及抗纤维化作用。本项目以AMPK与A-769662复合物的结构为模板，以JXD-002为先导，开展基于结构的药物设计、构效关系及作用机制研究，期望在吡唑并吡啶酮类AMPK激活剂的基础研究方面取得创新性成果，并获得活性更强、成药性更好的慢性肾病治疗候选药物。

在高能量状态下，腺苷酸活化蛋白激酶（AMPK）活性被抑制，引起两种重要标记物NF-κB（炎症）和TGF-β（纤维化）活性异常，引发肾脏持续的炎症及纤维化，最终导致终末期肾衰。因此，AMPK成为CKD药物研发的重要靶点。本项目以AMPK与A-769662复合物的结构为模板，以JXD-002为先导，设计、合成了多个系列近300个吡唑并吡啶酮类化合物，测试了其AMPK激活作用，检测了化合物对成纤维细胞增殖抑制活性发现大部分化合物具有良好的抗纤维化潜力，进一步机制研究发现这类AMPK激活剂可能通过TGF-β 及NF-κB 通路，而发挥治疗慢性肾病或者相关疾病的作用。本研究为为AMPK激活剂治疗慢性肾病的基础研究提供了有意义的信息，为发现成药性更好治疗候选药物提供了一定物质基础。