Dousson Cyril B
Idenix, an MSD Company-Medicinal Chemistry Cap Gamma, Montpellier, France.
Antivir Chem Chemother. 2018 Jan-Dec;26:2040206618756430. doi: 10.1177/2040206618756430.
This review describes the current state of discovery of past most important nucleoside and nucleotide prodrugs in the treatment of hepatitis C virus infection as well as future potential drugs currently in discovery or clinical evaluation. I highlight first generation landmark prodrug compounds which have been the foundations of incremental improvements toward the discovery and approval milestone of Sofosbuvir. Sofosbuvir is the first nucleotide prodrug marketed for hepatitis C virus treatment and the backbone of current combination therapies. Since this approval, new nucleotide prodrugs using the same design of Sofosbuvir McGuigan prodrug have emerged, some of them progressing through advanced clinical trials and may become available as new incremental alternative hepatitis C virus treatments in the future. Although since Sofosbuvir success, only minimal design efforts have been invested in finding better liver targeted prodrugs, a few novel prodrugs are being studied and their different modes of activation may prove beneficial over the heart/liver targeting ratio to reduce potential drug-drug interaction in combination therapies and yield safer treatment to patients. Prodrugs have long been avoided as much as possible in the past by development teams due to their metabolism and kinetic characterization complexity, but with their current success in hepatitis C virus treatment, and the knowledge gained in this endeavor, should become a first choice in future tissue targeting drug discovery programs beyond the particular case of nucleos(t)ide analogs.
本综述描述了过去在丙型肝炎病毒感染治疗中最重要的核苷和核苷酸前药的发现现状，以及目前正在研发或处于临床评估阶段的未来潜在药物。我重点介绍了第一代具有里程碑意义的前药化合物，它们是朝着索磷布韦的发现和批准里程碑逐步改进的基础。索磷布韦是首个上市用于治疗丙型肝炎病毒的核苷酸前药，也是当前联合疗法的核心药物。自获批以来，采用与索磷布韦 - 麦吉根前药相同设计的新型核苷酸前药不断涌现，其中一些已进入晚期临床试验，未来可能成为丙型肝炎病毒治疗的新的渐进性替代药物。尽管自索磷布韦取得成功以来，在寻找更好的肝脏靶向性前药方面投入的设计工作很少，但仍有一些新型前药正在研究中，它们不同的激活方式可能在心脏/肝脏靶向率方面具有优势，从而减少联合疗法中潜在的药物相互作用，并为患者提供更安全的治疗。过去，开发团队一直尽可能避免使用前药，因为它们的代谢和动力学特性复杂，但鉴于其目前在丙型肝炎病毒治疗中的成功，以及在此过程中获得的知识，在前体药物发现计划中，除了核苷（酸）类似物这种特殊情况外，前药应成为未来组织靶向药物发现计划的首选。
