Evidence indicates that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in its replication, and cyclophilin inhibitors represent a new class of anti-HCV agents. We have established an efficient synthetic methodology to generate FR901459 derivatives via N, O-acyl migration reaction while avoiding total synthesis. Through a detailed structure–activity relationship study, we improved anti-HCV activity while decreasing immunosuppressive activity. Additionally, we discovered the importance of substitution at the 3 position for not only improving anti-HCV activity but also pharmacokinetic profile. Finally, by striking an appropriate balance between potency, solubility, and permeability, we discovered ASP5286 (13) as a potential clinical candidate for anti-HCV therapy.

有证据表明，丙型肝炎病毒（HCV）在复制过程中利用了细胞亲环蛋白，而亲环蛋白抑制剂代表了一类新的抗HCV药物。我们建立了一种有效的合成方法，可通过N，O-酰基迁移反应生成FR901459衍生物，同时又避免了全合成。通过详细的结构-活性关系研究，我们提高了抗HCV活性，同时降低了免疫抑制活性。此外，我们发现在3位取代的重要性不仅可以提高抗HCV活性，而且还可以改善药代动力学。最后，通过在效力，溶解度和渗透性之间取得适当的平衡，我们发现ASP5286（13）可作为抗HCV治疗的潜在临床候选药物。