A research effort focused on synthesis of novel 2'-dihalogenated nucleosides has identified 2'-a-bromo-2'-b-chloro-uridine as a potent inhibitor of HCV NS5B polymerase. The standard 5'-phosphoramidate prodrug of this nucleoside, which has the alanine isopropyl ester that has been utilized to deliver several nucleoside HCV inhibitors that have been studied in the clinic, is a potent, pan-genotypic inhibitor in replicon assays. However, pharmacokinetic studies in dog revealed low levels of the active nucleoside triphosphate were present in the liver following oral administration of this compound. We synthesized new prodrugs of this nucleoside and evaluated their potential to deliver the triphosphate metabolite in human hepatocytes. Promising analogs were then tested in the dog liver biopsy study. This method identified a 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug that provided &gt;10-fold improvement in triphosphate levels in dog liver at both 4 and 24 hours following oral dosing in comparison to the standard phosphoramidate prodrug. Further studies revealed that the AIBEE phosphoramidate can be used to provide high liver triphosphate levels for other nucleoside HCV inhibitors, and thus may provide HCV inhibitors with increased efficacy compared to compounds currently being used in the clinic.

Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs that deliver high levels of the active triphosphate of nucleoside HCV inhibitors in human hepatocytes and in dog liver biopsy studies

256th National Meeting (2018)

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