Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.

Autor: Chris Krueger A; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: a.chris.krueger@abbvie.com., Chen HJ; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States. Electronic address: hui-ju.chen@abbvie.com., Randolph JT; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Brown BS; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Halvorsen GT; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Heyman HR; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Li T; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Marvin CC; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Shanley JP; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Voight EA; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Bow DAJ; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Van Handel C; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Peterkin V; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Carr RA; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Stolarik D; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Dekhtyar T; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Irvin ML; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Krishnan P; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Henry RF; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., Wagner R; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States., DeGoey DA; AbbVie Incorporated, Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL 60064, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Jan 01; Vol. 28 (1), pp. 115208. Date of Electronic Publication: 2019 Nov 11.
DOI: 10.1016/j.bmc.2019.115208
Abstrakt: Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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