The application of the phosphoramidate ProTide approach confers micromolar potency against Hepatitis C virus on inactive agent 4′-azidoinosine: Kinase bypass on a dual base/sugar modified nucleoside

• Published in: Bioorganic & medicinal chemistry letters 2009-06, Vol.19 (11), p.3122-3124
• Main Authors: McGuigan, Christopher, Daverio, Felice, Nájera, Isabel, Martin, Joseph A., Klumpp, Klaus, Smith, David B.
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - toxicity; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - toxicity; Azides - chemical synthesis; Azides - chemistry; Biological and medical sciences; Drug Discovery; HCV; Hepacivirus - drug effects; Hepatitis C virus; Inosine - analogs & derivatives; Inosine - chemical synthesis; Inosine - chemistry; Medical sciences; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleotides; Pharmacology. Drug treatments; Phosphoric Acids - chemical synthesis; Phosphoric Acids - chemistry; Phosphoric Acids - toxicity; Prodrugs; Protides
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.03.138

4′-Azidoinosine is inactive versus HCV, while its Pro Tides are active at μM levels. Novel phosphoramidate ProTides derived from 4′-azidoinosine have been prepared and evaluated in the replicon assay against hepatitis C Virus (HCV). The parent nucleoside analogue is inactive in this assay, while the ProTides are active at low μM levels in some cases. This is a rare example of an inosine nucleoside analogue with potent antiviral activity and further supports the notion of ProTides as a drug discovery motif.