Title of article :
Novel HCV NS5B polymerase inhibitors derived from 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-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
Author/Authors :
Liansheng Li، نويسنده , , Yuefen Zhou، نويسنده , , Douglas E. Murphy، نويسنده , , Nebojsa Stankovic، نويسنده , , Jingjing Zhao، نويسنده , , Peter S. Dragovich and Shella A. Fuhrman، نويسنده , , Thomas Bertolini، نويسنده , , Zhongxiang Sun، نويسنده , , Benjamin Ayida، نويسنده , , Chinh V. Tran، نويسنده , , Frank Ruebsam، نويسنده , , Stephen E. Webber، نويسنده , , Amit M. Shah، نويسنده , , Mei Tsan، نويسنده , , Richard E. Showalter، نويسنده , , Rupal Patel، نويسنده , , Laurie A. LeBrun، نويسنده , , Darian M. Bartkowski، نويسنده , , Thomas G. Nolan، نويسنده , , Daniel A. Norris، نويسنده , , et al.، نويسنده ,
Abstract :
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 t1/2 > 60 min), and high ratios of liver to plasma concentrations 12 h after a single oral administration to rats.
Keywords :
Pyridazinones , 5-Hydroxy-3(2H)-pyridazinone derivatives , Hepatitis C virus (HCV) , RNA-dependent RNA polymerase (RdRp) , Small molecule , DMPK profiling , Ratio of liver to plasma concentration , Non-nucleoside NS5B inhibitors
