2. Academic Validation
  3. An O-Benzyl Phosphonamidate Prodrug of Tenofovir for the Treatment of Hepatitis B Virus Infection

An O-Benzyl Phosphonamidate Prodrug of Tenofovir for the Treatment of Hepatitis B Virus Infection

  • J Med Chem. 2022 Jul 14;65(13):9493-9505. doi: 10.1021/acs.jmedchem.2c00869.
Qianqian Zhang 1,  Youmei Peng 2,  Jiao Hou 1,  Yanhong Chen 3,  Bingjie Liu 3,  Pinghu Zhang 4,  Wenquan Yu 1,  Junbiao Chang 1 5 3
Affiliations

Affiliations

  • 1 Green Catalysis Center and College of Chemistry, Zhengzhou University, Zhengzhou, Henan 450001, China.
  • 2 Henan Key Laboratory for Pharmacology of Liver Diseases, Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
  • 3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 4 Institute of Translational Medicine & Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical College, Yangzhou University, Yangzhou 225009, China.
  • 5 NMPA Key Laboratory for Research and Evaluation of Innovative Drug, Henan Normal University, Xinxiang 453007, China.
PMID: 35776695 DOI: 10.1021/acs.jmedchem.2c00869
Abstract

A series of new O-(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 o-methylbenzyl group (1a) has the most potent in vitro anti-HBV activity. This prodrug (1a) was well-tolerated in KM mice via intragastric administration at a dosage of up to 1.5 g/kg. In DHBV-infected ducks, prodrug 1a 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 1a 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.

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