Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 13, Pages 9493-9505Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00869
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Funding
- National Natural Science Foundation of China [81773570, 82130103, U1804283]
- Young Backbone Teachers Fund of Henan Province [2021GGJS012]
- Key Scientific and Technological Project of Henan Province [202102310159]
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This research designed and synthesized a series of new O-(substituted benzyl) phosphoramidate prodrugs for the treatment of HBV infections. Prodrug 1a showed the most potent anti-HBV activity and demonstrated good tolerability in experimental animals. It exhibited significant inhibitory effect on viral replication without causing liver damage.
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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