- Synthesis and biological effects of new 3-alkylamino-4H-1,2,4- benzothiadiazine 1,1-dioxides on insulin-secreting cells
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3-Alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides with nitro, amino or acetylamino groups in the 7-position have been synthesized in an attempt to discover new tissue-selective K(ATP)-channel openers. The compounds were tested as putative pancreatic β-cells K(ATP)-channel openers by measuring their inhibitory activity on the insulin releasing process. The influence of the substituent in the 7-position on the acidic character (pK(a)) and on biological activity is discussed. The nitrobenzene derivatives were biologically active, but less so than the un-derivatized parent pyridothiadiazine dioxides.
- Somers, Fabian,De Tullio,Boverie,Dogne,De Leval,Antoine,Lebrun,Pirotte
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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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- A NOVEL PROCESS FOR THE PREPARATION OF N-(4-NITRO-2-SULFAMOYL-PHENYL)-MALONAMIC ACID METHYL ESTER AND N-(4-AMINO-2-SULFAMOYL-PHENYL)-MALONAMIC ACID METHYL ESTER
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The present invention provides a novel method for preparing compounds N-(4-nitro-2-sulfamoyl-phenyl)-malonamic acid methyl ester and N-(4-amino-2-sulfamoyl-phenyl)-malonamic acid methyl ester, which are novel intermediates for preparing a key intermediate
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Paragraph 0051-0055
(2014/07/23)
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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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p. 2455 - 2478
(2012/05/05)
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- NOVEL INHIBITORS OF HEPATITIS C VIRUS REPLICATION
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The embodiments provide compounds of the general Formulae I, II, III, IV, or V as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
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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
(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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- 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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- 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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- 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 70-71
(2008/12/06)
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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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- 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; 171
(2008/12/07)
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- 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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p. 2735 - 2738
(2008/12/21)
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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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- 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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- 5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity.
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AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 microM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 5'-position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 5'-ethyl derivative exhibited an EC(50) value in the order of 22 microM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC(50) value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 5'-ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure--activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor--drug interactions.
- Phillips, Dean,Sonnenberg, Jennifer,Arai, Amy C,Vaswani, Rishi,Krutzik, Peter O,Kleisli, Thomas,Kessler, Markus,Granger, Richard,Lynch, Gary,Richard Chamberlin
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p. 1229 - 1248
(2007/10/03)
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- 1,2,4-benzothiadiazine derivatives, their preparation and use
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1,2,4-Benzothiadiazine derivatives represented by formula wherein D, R1, R2, R3, R4, R5, R12, R13, R14, R15 are defined in the description, composition thereof and methods for preparing the compounds are described.The compounds are useful in the treatment of diseases of the central nervous system, the cardiovascular system, the pulmonary system, the gastrointestinal system and the endocrinological system.
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