Green Catalysis Center and College of Chemistry, Zhengzhou University, Zhengzhou, Henan 450001, China.
Henan Key Laboratory for Pharmacology of Liver Diseases, Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
J Med Chem. 2022 Jul 14;65(13):9493-9505. doi: 10.1021/acs.jmedchem.2c00869. Epub 2022 Jul 1.
A series of new -(substituted benzyl) phosphoramidate prodrugs of tenofovir for the treatment of hepatitis B virus (HBV) infections have been designed and synthesized. An investigation of structure-activity relationships revealed that the compound bearing an -methylbenzyl group () has the most potent anti-HBV activity. This prodrug () was well-tolerated in KM mice via intragastric administration at a dosage of up to 1.5 g/kg. In DHBV-infected ducks, prodrug displayed a good inhibitory effect on the viral DNA replication in both the serum and the liver in a time- and dose-dependent manner and did not cause any necrosis, hemorrhage, or inflammatory response in the animal livers. Further investigation demonstrated that prodrug achieved a higher exposure of the bioactive metabolite (tenofovir diphosphate, TFV-DP) in the liver, the target organ for the treatment of HBV infection, than tenofovir alafenamide fumarate (TAF) did at an equimolar dose.
我们设计并合成了一系列新型的替诺福韦（取代苄基）磷酰胺前药，用于治疗乙型肝炎病毒（HBV）感染。构效关系研究表明，含有 - 甲基苄基的化合物（）具有最强的抗 HBV 活性。该前药（）在 KM 小鼠中经灌胃给药，剂量高达 1.5 g/kg 时耐受性良好。在 DHBV 感染的鸭子中，前药在时间和剂量依赖性方式下对血清和肝脏中的病毒 DNA 复制均显示出良好的抑制作用，并且在动物肝脏中未引起任何坏死、出血或炎症反应。进一步的研究表明，与富马酸替诺福韦艾拉酚胺（TAF）相比，前药在治疗 HBV 感染的靶器官肝脏中实现了更高的活性代谢物（替诺福韦二磷酸，TFV-DP）暴露。
