Parallel synthesis of pteridine derivatives as potent inhibitors for hepatitis C virus NS5B RNA-dependent RNA polymerase.
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 microM. 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.
Ding
Yili
Y
Valeant Pharmaceuticals International, 3300 Hyland Avenue Costa Mesa, CA 92626, USA. yding@icnpharm.com
Girardet
Jean-Luc
JL
Smith
Kenneth L
KL
Larson
Gary
G
Prigaro
Brett
B
Lai
Vicky C H
VC
Zhong
Weidong
W
Wu
Jim Z
JZ
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D011621:Pteridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D011621:Pteridines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase