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Synthesis and Anti-Hepatitis B Activities of 3'-Fluoro-2'-Substituted Apionucleosides. 2022
Martin Holan, and
Kathryn Tucker, and
Natalia Dyatkina, and
Hong Liu, and
April Kinkade, and
Guangyi Wang, and
Zhinan Jin, and
Marija Prhavc
Janssen Research and Development, LLC, South San Francisco, CA 94080, USA.
Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2'-hydroxy- and 2'-hydroxymethyl-apionucleosides, 4 and 5, corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2'-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC50 value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC50 value of 7.8 nM.
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