- Des-A-ring benzothiadiazines: Inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase
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In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methyl
- Donner, Pamela L.,Xie, Qinghua,Pratt, John K.,Maring, Clarence J.,Kati, Warren,Jiang, Wen,Liu, Yaya,Koev, Gennadiy,Masse, Sherie,Montgomery, Debra,Molla, Akhter,Kempf, Dale J.
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Read Online
- Efficient large-scale synthesis of 2-amino-5- methanesulfonylaminobenzenesulfonamide
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A novel synthesis of 2-amino-5-methanesulfonylaminobenzenesulfonamide is described. This preparation begins with readily available 4-nitroaniline and proceeds through five steps (isolations) in 41% overall yield. The described chemistry is conducted on a 50- to 100-g scale and does not require extractive workup procedures or chromatographic purifications. Copyright Taylor & Francis Group, LLC.
- Dragovich, Peter S.,Murphy, Douglas E.,Tran, Chinh V.,Ruebsam, Frank
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Read Online
- FUSED [1,2,4]THIADIAZINE DERIVATIVES WHICH ACT AS KAT INHIBITORS OF THE MYST FAMILY
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A compound of formula (I): which inhibits the activity of one or more KATs of the MYST family, i.e., TIP60, KAT6B, MOZ, HBO1 and MOF.
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Page/Page column 188
(2019/03/17)
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- Integrated structure-based activity prediction model of benzothiadiazines on various genotypes of HCV NS5b polymerase (1a, 1b and 4) and its application in the discovery of new derivatives
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This work presents the first structure-based activity prediction model for benzothiadiazines against various genotypes of HCV NS5b polymerase (1a, 1b and 4).The model is a comprehensive workflow of structure-based field template followed by guided docking. The field template was used as a pre-filter and a tool to provide hits in good orientation and position. It was created based on detailed molecular interaction field analysis which includes Topomer CoMFA, grid independent analysis and Superstar. On the other hand, Guided docking was used as a refinement and assessment tool. It was actively directed by two scores: Moldock score as an interaction descriptor (r2 = 0.65) and a template similarity score as a measure for accurate binding-mode compliance. The docking template was based on energy-based pharmacophore analysis. The whole procedure was formulated and tweaked for both screening (ROC of AUC = 0.91) and activity prediction (r2 of 0.8) for the genotype 1a. In order to widen the model scope, linear interaction energy was used as a tool for predicting activities of other genotypes based on the docked ligand poses while mutation binding energy was used to investigate the effect of each amino acid mutation in genotype 4. The model was applied for structure-based fragment hopping by screening a library designed by reaction enumeration. A top scoring hit was used to generate a focused library such that it has lower TPSA than the original class ligands and thus better pharmacokinetic properties. After that, experimental validation was carried out by the synthesis of this library and its biological evaluation which yielded compounds that exhibit EC50 ranging from 1.86 to 23 μM.
- Ismail, Mohamed A.H.,Abou El Ella, Dalal A.,Abouzid, Khaled A.M.,Mahmoud, Amr H.
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supporting information; experimental part
p. 2455 - 2478
(2012/05/05)
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- A METHOD OF INHIBITING HEPATITIS C VIRUS BY COMBINATION OF A 5,6-DIHYDRO-1H-PYRIDIN-2-ONE AND ONE OR MORE ADDITIONAL ANTIVIRAL COMPOUNDS
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The invention is directed to a method of treating infections by hepatitis C virus by administering N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1 -dioxo-l,4-dihydro-lλ6- benzo[l,2,4]thiadiazin-7-yl} -methanesulfonamide and one or more additional antiviral compounds or pharmaceutical compositions containing such compounds.
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Page/Page column 36-37
(2010/04/28)
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- 4-Hydroxy-5,6-dihydro-1H-pyridin-2-one compounds
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The invention is directed to 4-hydroxy-5,6-dihydro-1H-pyridin-2-one compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 20
(2009/04/24)
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- 5,6-DIHYDRO-1H-PYRIDIN-2-ONE COMPOUNDS
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The invention is directed to 5,6-dihydro-lH-pyridin-2-one compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 70
(2008/12/04)
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- 5,6-DIHYDRO-1H-PYRIDIN-2-ONE COMPOUNDS
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The invention is directed to 5,6-dihydro-1H-pyridin-2-one compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 71
(2008/12/06)
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- SATURATED FUSED [1,2-B] PYRIDAZINONE COMPOUNDS
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The invention is directed to saturated fused [1,2-b]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 51
(2008/12/06)
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- 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 128-129
(2008/12/07)
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- 5,5-DISUBSTITUTED-INDOLIZINONE COMPOUNDS
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The invention is directed to 5,5-disubstituted-indolizinone compounds and pharmaceutical compositions containing such compounds that are useful in treating infections by hepatitis C virus.
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Page/Page column 23
(2008/12/07)
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- Hepatitis C NS5B polymerase inhibitors: 4,4-Dialkyl-1-hydroxy-3-oxo-3,4-dihydronaphthalene-3-yl benzothiadiazine derivatives
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4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
- Hutchinson, Douglas K.,Rosenberg, Teresa,Klein, Larry L.,Bosse, Todd D.,Larson, Daniel P.,He, Wenping,Jiang, Wen W.,Kati, Warren M.,Kohlbrenner, William E.,Liu, Yaya,Masse, Sherie V.,Middleton, Tim,Molla, Akhteruzzaman,Montgomery, Debra A.,Beno, David W.A.,Stewart, Kent D.,Stoll, Vincent S.,Kempf, Dale J.
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scheme or table
p. 3887 - 3890
(2009/04/07)
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- PYRRO[1,2-B]PYRIDAZINONE COMPOUNDS
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The invention is directed to pyrro[l,2-b]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 54; 115
(2008/06/13)
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- Inhibitors of HCV NS5B polymerase: Synthesis and structure-activity relationships of unsymmetrical 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives
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Substituted 1-hydroxy-4,4-dialkyl-3-oxo-3,4-dihydronaphthalene benzothiadiazine derivatives were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed. It was found that
- Krueger, A. Chris,Madigan, Darold L.,Green, Brian E.,Hutchinson, Douglas K.,Jiang, Wen W.,Kati, Warren M.,Liu, Yaya,Maring, Clarence J.,Masse, Sherie V.,McDaniel, Keith F.,Middleton, Tim R.,Mo, Hongmei,Molla, Akhteruzzaman,Montgomery, Debra A.,Ng, Teresa I.,Kempf, Dale J.
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p. 2289 - 2292
(2008/02/13)
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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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Page/Page column 75
(2008/06/13)
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- ANTI-INFECTIVE AGENTS
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Compounds having the formula (I) 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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Page/Page column 151
(2010/02/11)
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