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
  • 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.