Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ 6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2 H-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) < 10 nM; IC 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.