Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 8, Pages 5802-5819Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00046
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Early antiviral treatments, including intravenous remdesivir (RDV), have been effective in reducing hospitalization and severe disease caused by COVID-19. Researchers have developed an orally bioavailable RDV analog, called RVn, which shows promise in reducing lung viral load in mice infected with SARS-CoV-2. Further evaluation of different analogs with hydrophobic ethers at the sn-2 of glycerol has identified potential improvements in antiviral activity. These findings support the development of RVn phospholipid prodrugs as oral antiviral agents for the prevention and treatment of SARS-CoV-2 infections.
Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by 1.5 log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro antiviral activity by introduction of a 3-fluoro-4-methoxy-substituted benzyl or a 3-or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections.
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