Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors.
From chemical compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a substituted quinoxaline hit with an IC(50) of 5.5 microM. A series of substituted quinoxaline amide derivatives were synthesized based on the hit's pharmacophore, and a good structure-activity relationship was observed. Computer modeling analysis was employed to help comprehend the SAR.
Rong
Frank
F
Drug Discovery, Valeant Pharmaceutical Research & Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. frong@ardeabiosciences.com
Chow
Suetying
S
Yan
Shunqi
S
Larson
Gary
G
Hong
Zhi
Z
Wu
Jim
J
D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D008958:Models, Molecular; D011485:Protein Binding; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011810:Quinoxalines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase