Discovery of 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs for delivering nucleoside HCV NS5B polymerase inhibitors

  • Bioorg Med Chem Lett. 2020 Apr 1;30(7):126986. doi: 10.1016/j.bmcl.2020.126986.
John T Randolph  1 ,  Tongmei Li  1 ,  A Chris Krueger  1 ,  Howard R Heyman  1 ,  Hui-Ju Chen  1 ,  Daniel A J Bow  1 ,  Cecilia Van Handel  1 ,  Vincent Peterkin  1 ,  Robert A Carr  1 ,  DeAnne Stolarik  1 ,  Tatyana Dekhtyar  1 ,  Michelle Irvin  1 ,  Preethi Krishnan  1 ,  Rolf Wagner  1 ,  David A DeGoey  1
Affiliations
  • 1. Abbvie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States.
PMID: 32046903 DOI: 10.1016/j.bmcl.2020.126986
Abstract

Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose).

Keywords
Antiviral; HCV; Nucleoside; Phosphoramidate; Prodrug.