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 5: Exploration of pyridazinones containing 6-amino-substituents
Author/Authors :
Peter S. Dragovich and Shella A. Fuhrman، نويسنده , , Julie K. Blazel، نويسنده , , David A. Ellis، نويسنده , , Qing Han، نويسنده , , Ruhi Kamran، نويسنده , , Charles R. Kissinger، نويسنده , , Laurie A. LeBrun، نويسنده , , Liansheng Li، نويسنده , , Douglas E. Murphy، نويسنده , , Michael Noble، نويسنده , , Rupal A. Patel، نويسنده , , Frank Ruebsam، نويسنده , , Maria V. Sergeeva، نويسنده , , Amit M. Shah، نويسنده , , Richard E. Showalter، نويسنده , , Chinh V. Tran، نويسنده , , Mei Tsan، نويسنده , , Stephen E. Webber، نويسنده , , Leo Kirkovsky، نويسنده , , Yuefen Zhou، نويسنده ,
Abstract :
The synthesis of 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 < 0.10 μM). In vitro DMPK data (microsome t1/2, Caco-2 Papp) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
Keywords :
Hepatitis C virus (HCV) , RNA-dependent RNA polymerase (RdRp) , Non-nucleoside NS5B inhibitors , Pyridazinones , 5-Hydroxy-3(2H)-pyridazinone derivatives
