- PYRIDAZINONE COMPOUNDS
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The invention is directed to pyridazinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 80
(2010/11/08)
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- 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase
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Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
- Tedesco, Rosanna,Shaw, Antony N.,Bambal, Ramesh,Chai, Deping,Concha, Nestor O.,Darcy, Michael G.,Dhanak, Dashyant,Fitch, Duke M.,Gates, Adam,Gerhardt, Warren G.,Halegoua, Dina L.,Han, Chao,Hofmann, Glenn A.,Johnston, Victor K.,Kaura, Arun C.,Liu, Nannan,Keenan, Richard M.,Lin-Goerke, Juili,Sarisky, Robert T.,Wiggall, Kenneth J.,Zimmerman, Michael N.,Duffy, Kevin J.
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p. 971 - 983
(2007/10/03)
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- Inhibitors of HCV NS5B polymerase: Synthesis and structure-activity relationships of N-1-benzyl and N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine analogs containing substituents on the aromatic ring
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A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.
- Rockway, Todd W.,Zhang, Rong,Liu, Dachun,Betebenner, David A.,McDaniel, Keith F.,Pratt, John K.,Beno, David,Montgomery, Debra,Jiang, Wen W.,Masse, Sherie,Kati, Warren M.,Middleton, Tim,Molla, Akhteruzzaman,Maring, Clarence J.,Kempf, Dale J.
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p. 3833 - 3838
(2007/10/03)
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- Anti-infective agents
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Compounds having the formula are hepatitis C (HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C (HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.
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- Anti-infective agents
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Compounds having the formula are hepatitis C(HCV) polymerase inhibitors. Also disclosed are a composition and method for inhibiting hepatitis C(HCV) polymerase, processes for making the compounds, and synthetic intermediates employed in the processes.
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- Recyclization of 2-imino-2H-1-benzopyrans under the influence of nucleophilic reagents. 2. Reaction of 2-iminocoumarin-3-carboxamides with o-aminobenzenesulfonamide
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2-Iminocoumarin-3-carboxamides recyclized into 3-(1,1-dioxo-2H-benzo-1,2,4-thiadiazinyl-3)coumarins under the influence of o-aminobenzenesulfonamide. An alternative method of synthesis is discussed. Proposed mechanisms for the recyclization are discussed.
- Kovalenko,Chernykh,Shkarlat,Ukrainets,Gridasov,Rudnev
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p. 791 - 795
(2007/10/03)
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