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 5: Exploration of pyridazinones containing 6-amino-substituents |
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Authors: | Dragovich Peter S Blazel Julie K Ellis David A Han Qing Kamran Ruhi Kissinger Charles R LeBrun Laurie A Li Lian-Sheng Murphy Douglas E Noble Michael Patel Rupal A Ruebsam Frank Sergeeva Maria V Shah Amit M Showalter Richard E Tran Chinh V Tsan Mei Webber Stephen E Kirkovsky Leo Zhou Yuefen |
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Institution: | Anadys Pharmaceuticals, Inc., 3115 Merryfield Row, San Diego, CA 92121, USA. pdragovich@anadyspharma.com |
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Abstract: | The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo1',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 (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed. |
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