Synthesis of 9-(2-β- C-methyl-β- d-ribofuranosyl)-6-substituted purine derivatives as inhibitors of HCV RNA replication

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 3; pp. 709 - 713
• Main Authors: Ding, Yili, Girardet, Jean-Luc, Hong, Zhi, Lai, Vicky C.H., An, Haoyun, Koh, Yung-hyo, Shaw, Stephanie Z., Zhong, Weidong
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-02-2005; Elsevier
• Subjects: 2- C-Methyl nucleoside; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Biological and medical sciences; Cell Line; HCV; Hepacivirus - genetics; Humans; Inhibitors; Medical sciences; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Purine Nucleosides - chemical synthesis; Purine Nucleosides - pharmacology; Replicon - drug effects; RNA, Viral - drug effects; RNA, Viral - genetics; Structure-Activity Relationship; Virus Replication - drug effects; 2- C-Methyl nucleoside; HCV; Inhibitors; Purine nucleotide; RNA; Metabolite; Prodrug; Branched compound; In vitro; Virus; Structure activity relation; Antiviral; Replication; Inhibitor; Intracellular; Flaviviridae; Chemical synthesis; Hepatitis C virus; Hepacivirus
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.11.020

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A series of 9-(2′-β-
C-methyl-β-
d-ribofuranosyl)-6-substituted purine derivatives were synthesized as potential inhibitors of HCV RNA replication. Their inhibitory activities in a cell based HCV replicon assay were reported. A prodrug approach was used to further improve the potency of these compounds by increasing the intracellular levels of 5′-monophosphate metabolites. These nucleotide prodrugs showed much improved inhibitory activities of HCV RNA replication.