Phosphoramidate prodrugs have played an important role in research to identify nucleoside inhibitors of HCV polymerase due to their ability to deliver the parent drug to the liver for efficient conversion to the active triphosphate metabolite. A research program to investigate novel HCV-active nucleosides identified 2’-dihalogenated uridine analogs with good potency in genotype 1 replicon assays. However, an early lead containing the L-alanine isopropyl ester phosphoramidate prodrug moiety used with success in the clinic to deliver multiple HCV nucleoside inhibitors, including sofosbuvir (SOF), was found to provide low levels of the active nucleoside 5’-triphosphate (NTP) in liver when dosed orally in dogs. Alternative phosphoramidate prodrugs were screened using an assay developed to measure NTP concentrations in human hepatocytes to assess both bioactivation efficiency and persistence of the active species. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs which provide high NTP concentrations in comparison to nucleosides bearing the standard prodrug moiety.  PK studies in dog, collecting liver biopsy samples at 4 and 24 hours after oral dosing, found that AIBEE prodrugs provide high NTP concentrations at both time points in comparison to other phosphoramidate prodrugs. This research identified 2’-bromo,fluoro uridine analog ABBV-168 as a potential development candidate. The initial route to ABBV-168 was not stereocontrolled, so a second-generation synthesis was developed which improved both dihalogenated stereocenter selectivity (3:1 to 9:1) and uracil glycosylation stereoselectivity (1:9 to 5:1). A third-generation synthesis was then developed that required no tedious chromatographic purification, resulting in an enabling route to prepare quantities of ABBV-168 for use in the clinic.

2-Aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs deliver high concentrations of nucleoside 5’-triphosphate in human hepatocytes and dog liver biopsy studies: Application in the discovery of a novel 2’-dihalogenated nucleoside HCV polymerase inhibitor ABBV-168

ACS Fall 2021

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