Abstract：
Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC50 = 0.55 μM) in a hypoxia-reactive element (HRE) luciferase reporter assay. Further pharmacological studies revealed that 17q concentration-dependently blocked hypoxia-induced HIF-1α protein accumulation, reduced inflammation response, inhibited cellular invasiveness and promoted VHL-dependent HIF-1α degradation in human RA synovial cell line. Moreover, 17q improved the pathological injury of ankle joints, decreased angiogenesis and attenuated inflammation response in the adjuvant-induced arthritis (AIA) rat model, indicating the promising therapeutic potential of compound 17q as an effective HIF-1 inhibitor for RA therapy.
摘要：
由于滑膜缺氧微环境显著促进类风湿关节炎(RA)的病理进展,缺氧诱导因子1(HIF-1)已成为研发新型RA治疗药物的有希望的靶点.在这项研究中,我们使用支架跳跃策略设计并合成了一系列二芳基取代的异喹啉-1(2H)-酮衍生物作为HIF-1信号抑制剂。通过修饰异喹啉-1-酮的N原子和6位上的取代基，我们发现化合物17q在缺氧反应元件(HRE)荧光素酶报告基因测定中具有最有效的抗HIF-1活性(IC50=0.55μM)。进一步的药理学研究表明，17q浓度依赖性地阻断缺氧诱导的HIF-1α蛋白积累，减少炎症反应，在人RA滑膜细胞系中抑制细胞侵袭并促进VHL依赖性HIF-1α降解。此外，17q改善了踝关节的病理损伤，佐剂性关节炎(AIA)大鼠模型血管生成减少,炎症反应减弱,表明化合物17q作为RA治疗的有效HIF-1抑制剂具有良好的治疗潜力。
