Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.

Abstract 5-Hydroxy-3(2 H )-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 [IC 50 (1b)  50 (1a) = 22 nM; EC 50 (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.