Publication Date:
2019
Description:
〈p〉Publication date: Available online 11 November 2019〈/p〉
〈p〉〈b〉Source:〈/b〉 Bioorganic & Medicinal Chemistry〈/p〉
〈p〉Author(s): A. Chris Krueger, Hui-Ju Chen, John T. Randolph, Brian S. Brown, Geoff T. Halvorsen, Howard R. Heyman, Tongmei Li, Christopher C. Marvin, Jason P. Shanley, Eric A. Voight, Daniel A.J. Bow, Cecilia Van Handel, Vincent Peterkin, Robert A. Carr, DeAnne Stolarik, Tatyana Dekhtyar, Michelle L. Irvin, Preethi Krishnan, Rodger F. Henry, Rolf Wagner〈/p〉
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〈h5〉Abstract〈/h5〉
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〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961931689X-fx1.jpg" width="571" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉
〈p〉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 〈strong〉18a〈/strong〉 and 〈strong〉18c〈/strong〉, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 〈strong〉18c〈/strong〉 was compared with sofosbuvir (〈strong〉1〈/strong〉) 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, 〈strong〉18c〈/strong〉 provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (〈strong〉1〈/strong〉) at both biopsy time points, suggesting that 〈strong〉18c〈/strong〉 could be a highly effective agent for treating HCV infected patients in the clinic.〈/p〉
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〈div xml:lang="en"〉
〈h5〉Graphical abstract〈/h5〉
〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S096808961931689X-ga1.jpg" width="437" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉
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Print ISSN:
0968-0896
Electronic ISSN:
1464-3391
Topics:
Chemistry and Pharmacology
,
Medicine
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