苄基哌嗪类埃博拉病毒侵入抑制剂的药代性质优化与作用机制研究

Ebola virus (EBOV) is a highly pathogenic enveloped virus and the transmission of Ebola virus from infected primates to humans causes outbreaks of severe and often fatal hemorrhagic fever (lethality up to 50-90%). There’s no therapeutic method is approved by the FDA so far. Study of the infection mechanism of Ebola virus and identification of effective treatment methods is of extremely significance to the scientific and the whole society, and it is also an urgent task in the field of antiviral drugs research. Previous study of the applicant involved a series of benzyl piperazine derivatives as specific Ebola virus entry inhibitors. Some of them represent potent compounds against EBOV infection. However, the poor in-vitro pharmacokinetic profiles diminish their potential for clinical use. .Based on valuable results obtained from previous work, focusing on the metabolic vulnerable dipeptides as the linker in these molecules, in this program, four series of novel benzyl piperazine derivatives are designed by replacing the amide bonds by sulfamide or N-containing aromatic heterocyclic as privileged structures in medicinal chemistry. After synthesis, these target molecules will be evaluated by both in vitro anti-viral test and in vitro pharmacokinetic assay. By more detailed structure-activity relationships (SAR) and structure-metabolism relationships (SMR), we hope to find better drug candidates with balanced drug-like properties for further study in vivo. Besides, several photo-affinity probe molecules are designed, which will be used in the mechanism study to find how these compounds react in the process of EBOV entry into host cell.

埃博拉出血热，是一种由埃博拉病毒引起、具有极高致死率的人畜共患传染病，目前尚没有特效药物上市。探究埃博拉病毒的传播机制，并且开发出有效的治疗方法有着极其重大的科研与社会意义，也是抗病毒药物研究领域的当务之急。申请人参与开发的作用于埃博拉病毒侵入过程的苄基哌嗪类化合物具有纳摩尔水平的埃博拉病毒体外抑制活性，但较差的药代动力学性质限制了它的应用。.本课题根据前期大量工作基础，针对苄基哌嗪类埃博拉病毒侵入抑制剂分子中易于代谢的二酰胺链状结构，通过成环、生物电子等排体替换等多种药物化学策略，设计、合成四类代谢稳定性更强的化合物，通过体外活性实验、体外药代动力学评价系统性探讨分子整体物理化学性质、药物代谢性质和体外药理活性的关系，并寻求多方面性质平衡性提升，以期发现更加优秀的候选化合物用于进一步体内研究。另外，根据此类化合物设计了若干光亲和探针分子，将利用它们进一步研究小分子作用模式和病毒侵入机制。

在本项目的资助下，我们主要在三个方向开展了研究：针对苄基哌嗪类埃博拉病毒侵入抑制剂药代稳定性不佳的问题，设计合成40余个新型衍生物，经过体外抗病毒和人肝微粒体稳定性研究发现重要的构效关系信息及若干半衰期大大延长，而活性得到一定保持的候选化合物，为进一步发现活性与成药性更佳的化合物奠定了基础。另外，我们利用液滴微阵列技术和多组分反应，初步构建了一种微型化高通量原位药物合成筛选平台，以微量的化学品消耗和高通量、固相合成和组合化学的方式大量合成、表征和生物测试数以千计的新化合物。这一平台可以应用于高通量筛选苄基哌嗪类埃博拉病毒侵入抑制剂及更多的药物发现场景。最后我们还针对乙型肝炎病毒衣壳组装调节剂磺酰胺苯甲酰胺类化合物NVR 3-778水溶性不足的问题，设计并合成了一系列含有羧酸、苯硼酸或苯硼酸酯的新型HBV衣壳组装调节剂。发现一个化合物7b具有与先导化合物相当的抗HBV活性，但溶解度大大提高，值得进一步向候选药物的方向开发。