Parallel synthesis of pteridine derivatives as potent inhibitors for hepatitis C virus NS5B RNA-dependent RNA polymerase

• Published in: Bioorganic & medicinal chemistry letters 2005-02, Vol.15 (3), p.675-678
• Main Authors: Ding, Yili, Girardet, Jean-Luc, Smith, Kenneth L., Larson, Gary, Prigaro, Brett, Lai, Vicky C.H., Zhong, Weidong, Wu, Jim Z.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; HCV; Hepacivirus - enzymology; Humans; Inhibitor; Inhibitory Concentration 50; Medical sciences; NS5B; Pharmacology. Drug treatments; Pteridine; Pteridines - chemical synthesis; Pteridines - pharmacology; Replicon - drug effects; RNA-Dependent RNA Polymerase - antagonists & inhibitors; Structure-Activity Relationship; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.11.028

[Display omitted] From compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a pteridine hit compound with an IC 50 of 15 μM. Our SAR studies were focused on the different groups at the 6- and 7-positions, substitutions at the 4-position, and replacement of N 1 or N 3 with carbon in the pteridine ring. We found that NH or OH at 4-position is critical for the inhibitory activity. Furthermore, a hydrophobic substituent at the 4-position may help compounds permeate through the cell membrane.