Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 11, Pages 3446-3455Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.02.072
Keywords
pyridazinones; 5-hydroxy-3(2H)-pyridazinone derivatives; hepatitis C virus (HCV); RNA-dependent RNA polymerase (RdRp); small molecule; non-nucleoside NS5B inhibitors; DMPK profiling; ratio of liver to plasma concentration
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5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC50 (1b) < 10 nM; IC50 (1a) = 22 nM; EC50 (1b) = 5 nM], good stability toward human liver microsomes (HLM t(1/2) > 60 min), and high ratios of liver to plasma concentrations 12 h after a single oral administration to rats. (c) 2008 Published by Elsevier Ltd.
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