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

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

Affiliation

  • 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.

Figures