- Design, Synthesis,In VitroandIn VivoCharacterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in down Syndrome
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Intracellular chloride concentration [Cl-]iis defective in several neurological disorders. In neurons, [Cl-]iis mainly regulated by the action of the Na+-K+-Cl-importer NKCC1 and the K+-Cl-exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 ( ARN24092 ) as a backup/follow-up lead within vivoefficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.
- Borgogno, Marco,Savardi, Annalisa,Manigrasso, Jacopo,Turci, Alessandra,Portioli, Corinne,Ottonello, Giuliana,Bertozzi, Sine Mandrup,Armirotti, Andrea,Contestabile, Andrea,Cancedda, Laura,De Vivo, Marco
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p. 10203 - 10229
(2021/07/19)
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- Controllable Soil Degradation Rate of 5-Substituted Sulfonylurea Herbicides as Novel AHAS Inhibitors
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Chlorsulfuron has been applied in wheat fields as a recognized herbicide worldwide, yet it was officially banned in China since 2014 for its soil persistence problem. On the basis of our previous research that 5-dimethylamino distinctively accelerated degradation rate in soils, a modified amino moiety (Ia-c) and monosubstituted amino group (Id-e) were introduced onto the fifth position of the benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents (If-g) to seek a suitable soil degradation rate during such an in situ crop rotation system. Referring to the biological data and ScAHAS inhibition and ScAHAS docking results, they turned out to be AHAS inhibitors with high potent herbicidal activities. The various influence on soil degradation rate along with crop safety indicated that different substituents on the fifth position have exerted an apparent impact. Their united study of structure-activity-safety-degradation relationship has great potential to provide valuable information for further development of eco-friendly agrochemicals.
- Chen, An-Liang,Chen, Jie,Hua, Xue-Wen,Li, Yong-Hong,Li, Zheng-Ming,Liu, Bin,Meng, Fan-Fei,Wang, Bao-Lei,Zhou, Shaa
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p. 3017 - 3025
(2020/03/31)
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- Research on the controllable degradation of: N -methylamido and dialkylamino substituted at the 5thposition of the benzene ring in chlorsulfuron in acidic soil
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Owing to the lengthy residual problems associated with chlorsulfuron, metsulfuron-methyl, and ethametsulfuron, which prevents them from being used in the "annual multi-crop planting system", the application of these sulfonylurea herbicides (SU) has regrettably been terminated in China since 2014. In this field, we were the first to discover that the 5th position of the benzene ring in chlorsulfuron is a key point for influencing its degradation rate and the amino moiety at this position showed faster degradation rates and maintained their original potent bioactivity. In this study, we further elaborated on N-methylamido and dialkylamino substituents at the same position in chlorsulfuron to obtain 18 novel structures as M and N series. Their half-life degradation (DT50) values were faster, to varying degrees, than chlorsulfuron in acidic soil. It was found that most of the titled structures also retained their potent herbicidal activity and the crop safety of the M series towards corn greatly increased. Based on these data, a comprehensive graph describing the structure/degradation relationship was established first. Relating to the new molecules, their herbicidal activity (A), degradation rates (D), and crop safety (S) relationship were correlated and we used this approach to predict and explore the most preferable molecule, which coincided to the corresponding experimental data. The new concept of controllable degradation will provide us with more insight when searching for new ecological bioactive molecules in the future.
- Chen, Ming-Gui,Gu, Yu-Cheng,Li, Yong-Hong,Li, Zheng-Ming,Ma, Yi,Meng, Fan-Fei,Wu, Lei,Zhao, Yang-Yang,Zhou, Sha,Zhou, Shaa
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p. 17870 - 17880
(2020/09/01)
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- MODULATORS OF INTRACELLULAR CHLORIDE CONCENTRATION
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The present invention relates to a compound of Formula la, lb and Ic, (Formula Ia) a pharmaceutical composition comprising the same and their use in the treatment or prevention of pathological conditions associated to depolarizing GABAergic transmission including, for example, Down syndrome and autism.
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- METHODS AND COMPOUNDS FOR TREATING PROLIFERATIVE DISORDERS AND VIRAL INFECTIONS
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The invention generally relates to methods and compounds for treating proliferative disorders, viral infections, or both. In some embodiments, the invention provides an anticancer or antiviral compound including a substituted nitro phenoxy phenyl, a sulfonylurea, and an alkyl group. In some embodiments, the invention provides a method of treating a proliferative disorder or a viral infection including administering an anticancer or antiviral compound that binds to a thromboxane receptor, has preferential binding for either TPalpha (TPα) or TPbeta (TPβ) receptor subtype.
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- Research on controllable degradation of sulfonylurea herbicides
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In order to seek ecologically safer and environmentally benign sulfonylurea herbicides (SU), insight into the structure/bioassay/soil degradation tri-factor relationship was first established. With the introduction of various groups (alkyl, nitro, halogen, cyano etc.) at the 5th position of its benzene ring, structural derivatives of chlorsulfuron were designed, synthesized, and evaluated for their herbicidal activity. The structures of the title compounds were confirmed by infrared spectroscopy, ultraviolet spectroscopy, 1H and 13C NMR, mass spectrometry, elemental analysis and X-ray diffraction. Bioassay results confirmed that most derivatives retained their superior herbicidal activities in comparison with chlorsulfuron. After investigating the soil degradation behavior of each molecule under set conditions, it was found that structures with electron-withdrawing substituents at the 5th position of the benzene ring retained their long degradation half-lives, yet the introduction of electron-donating substituents accelerated the degradation rate. These results will provide a valuable clue to further explore the potential controllable degradation of SU and other herbicides, and to discover novel herbicides that are favorable for environmentally and ecologically sustainable development.
- Hua, Xue-Wen,Chen, Ming-Gui,Zhou, Shaa,Zhang, Dong-Kai,Liu, Ming,Zhou, Sha,Liu, Jing-Bo,Lei, Kang,Song, Hai-Bin,Li, Yong-Hong,Gu, Yu-Cheng,Li, Zheng-Ming
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p. 23038 - 23047
(2016/03/12)
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- Controllable Effect of Structural Modification of Sulfonylurea Herbicides on Soil Degradation
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The study of soil degradation behaviors of sulfonylurea herbicides in relation to their different structural attributes is utmost important for us to comprehend the development of new eco-friendly herbicides. It is postulated that the structural modification of the chemical structures could influence their degradation rates in soil. Nine devised structures were synthesized to study their herbicidal activity as well as their soil degradation behaviors respectively. The novel compounds I-3–I-7 were characterized by UV,1H NMR and13C NMR, MS and EA. Bioassays indicated that most of target compounds displayed superior herbicidal activities in comparison with Chlorsulfuron. Soil degradation results further confirmed our previous assumption that the introduction of electron-donating substituents at 5thposition of the benzene ring distinctly increased their degradation rates, among which dimethylamino and diethylamino groups can adjust the degradation rate to a more favorable status.
- Hua, Xuewen,Zhou, Shaa,Chen, Minggui,Wei, Wei,Liu, Ming,Lei, Kang,Zhou, Sha,Li, Yonghong,Wang, Baolei,Li, Zhengming
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p. 1135 - 1142
(2016/11/25)
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- AROMATIC SULFONAMIDE DERIVATIVES
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Substituted aromatic sulfonamides of formula (I) pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
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Page/Page column 107
(2016/12/26)
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- NOVEL 4,6-DISUBSTITUTED AMINOPYRIMIDINE DERIVATIVES HAVING BOTH AROMATIC AND HALOGENIC SUBSTITUENTS
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Certain 4,6-disubstituted aminopyrimidine derivatives having both aromatic and halogenic substituents.
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Paragraph 0389; 0390
(2014/03/24)
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- 1,4,2-Benzo/pyridodithiazine 1,1-dioxides structurally related to the ATP-sensitive potassium channel openers 1,2,4-Benzo/pyridothiadiazine 1,1-dioxides exert a myorelaxant activity linked to a distinct mechanism of action
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The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2- benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a K ATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels.
- Pirotte, Bernard,De Tullio, Pascal,Florence, Xavier,Goffin, Eric,Somers, Fabian,Boverie, Stéphane,Lebrun, Philippe
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p. 3247 - 3256
(2013/06/05)
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- METHODS AND COMPOUNDS FOR TREATING PROLIFERATIVE DISORDERS AND VIRAL INFECTIONS
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The invention generally relates to methods and compounds for treating proliferative disorders, viral infections, or both. In some embodiments, the invention provides an anticancer or antiviral compound including a substituted nitro phenoxy phenyl, a sulfonylurea, and an alkyl group. In some embodiments, the invention provides a method of treating a proliferative disorder or a viral infection including administering an anticancer or antiviral compound that binds to a thromboxane receptor, has preferential binding for either TPalpha (TPα) or TPbeta (ΤΡβ) receptor subtype.
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- Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2 h -1,2,4-benzothiadiazine 1,1-dioxide scaffold
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Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a K d of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.
- N?rholm, Ann-Beth,Francotte, Pierre,Olsen, Lars,Krintel, Christian,Frydenvang, Karla,Goffin, Eric,Challal, Sylvie,Danober, Laurence,Botez-Pop, Iuliana,Lestage, Pierre,Pirotte, Bernard,Kastrup, Jette S.
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p. 8736 - 8745
(2013/12/04)
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- Synthesis and evaluation of novel monosubstituted sulfonylurea derivatives as antituberculosis agents
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A series of novel monosubstituted sulfonylurea derivatives 10a-y were synthesized and characterized by 1H NMR, 13C NMR and HRMS. These compounds were evaluated against Mycobacterium tuberculosis H37Rv in vitro. The results showed compounds 10f, 10k and 10s exhibited moderate antituberculosis activities with MIC values in the range of 20-100 mg/L. Compounds 10b and 10o displayed good antituberculosis activities (MIC 10 mg/L), which were comparable with that of the sulfometuron methyl. Both of the two compounds showed little cytotoxicities, with an IC50 against THP-1 cells greater than 100 mg/L.
- Pan, Li,Jiang, Ying,Liu, Zhen,Liu, Xing-Hai,Liu, Zhuo,Wang, Gang,Li, Zheng-Ming,Wang, Di
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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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- Cycloalkylated benzothiadiazines, a process for their preparation and pharmaceutical compostions containing them
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Compounds of formula (I): wherein: RCy represents an unsubstituted or substituted cycloalkyl group or cycloalkylalkyl group,R1, R2, R3 and R4, which may be the same or different, each represent a hydrogen or halogen atom or a nitro group; a cyano group; a hydroxy group; an alkoxy group; an alkyl group; an unsubstituted or substituted amino group; a carboxy group; an alkoxycarbonyl group; an aryloxycarbonyl group; an unsubstituted or substituted aminocarbonyl group. Medicinal products containing the same which are useful in treating or preventing conditions treatable by an AMPA receptor modulator.
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Page/Page column 13-14
(2010/02/17)
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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 34-35
(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 19-20
(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-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 68
(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 127; 171
(2008/12/07)
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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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- Design, synthesis, and SAR study of a series of N-alkyl-N′-[2- (aryloxy)-5-nitrobenzenesulfonyl]ureas and -cyanoguanidine as selective antagonists of the TPα and TPβ isoforms of the human thromboxane A2 receptor
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The prostanoid thromboxane (TX)A2 exerts its proaggregant and constrictive actions upon binding to the specific TXA2 receptor (TP), a member of the G-protein coupled receptor superfamily. In humans, TXA 2 signals through two distinct TP isoforms, TPα and TPβ. Herein, we describe the design, synthesis, and SAR study of a series of original N-alkyl-N′-[2-(aryloxy)-5-nitrobenzenesulfonyl]ureas and -cyanoguanidine. The SAR study was based on the results of a functional assay, TP-mediated intracellular calcium ([Ca2+]i) mobilization performed on the two separate isoforms. Optimal nature and position of several structural moieties was defined for both activity and selectivity toward TPα and TPβ isoforms. Three compounds (9h, 9af, and 9ag), showing increased selectivity for TPβ relative to TPα (23.2:1, 18.1:1, 19.9:1, respectively), were selected for further experiments, and their activity was confirmed in a platelet aggregation assay. This study represents the first extended SAR study dealing with the identification of isoform selective antagonists for the human TXA2 receptor.
- Hanson, Julien,Dogné, Jean-Michel,Ghiotto, Jérémie,Moray, Anne-Lise,Kinsella, B. Therese,Pirotte, Bernard
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p. 3928 - 3936
(2008/02/10)
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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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- Synthesis and pharmacological evaluation of novel nitrobenzenic thromboxane modulators as antiplatelet agents acting on both the alpha and beta isoforms of the human thromboxane receptor
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Thromboxane A2 (TXA2) is an arachidonic acid metabolite involved in pathologies such as stroke, myocardial infarction, and atherosclerosis. Consequently, the design of TXA2 receptor (TP) antagonists remains of great interest in cardiovascular medicine. The actions of TXA2 are mediated by its specific G-protein coupled receptor of which two alternative spliced isoforms, TPα and TPβ, have been described in humans. In this study, we report the synthesis of a series of original N-alkyl-N′-[2-(cycloalkyl, alkylaryl)-5-nitrobenzenesulfonyl]urea and N-alkyl-N′-[2-(alkylaryl)-5-nitrobenzenesulfonyl]-N″- cyanoguanidines and outline their pharmacological evaluation using the individual TPα and TPβ isoforms. Among compounds analyzed, several of them exhibited greater affinity and/or functional activity for either TPα or TPβ. The most promising molecules were also found to be antiplatelet agents. From the present results, structural features involved in isoform selectivity can be proposed, and thereby several lead compounds have been identified for the further development of selective TP isoform antagonists.
- Hanson, Julien,Reynaud, Denis,Qiao, Na,Devel, Philippe,Moray, Anne-Lise,Renard, Jean-Fran?ois,Kelley, Leanne P.,Winum, Jean-Yves,Montero, Jean-Louis,Kinsella, B. Therese,Pirotte, Bernard,Pace-Asciak, Cecil R.,Dogné, Jean-Michel
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p. 3701 - 3709
(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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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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- Benzene-sulphonamide derivatives and their uses
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Benzene-sulphonamide derivatives complying with the general formula (I): in which the different symbols have different meanings, their optical isomers and the salts pharmacologically acceptable of these derivatives, as well as their uses for drug manufacture and as radiolabelled pharmacological tools of the thromboxan A2 receptors.
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Page column 3-4; 5-7
(2010/02/09)
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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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- Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor
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The synthesis and the structure of N-isopropyl-N′-[2-(3′-methylphenylamino)-5-nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nM for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mM) and U-46619 (1 μM) with an IC50 value of 0.45 and 0.15 μM, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea-pig trachea precontracted by U-46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nM, respectively. Finally, 14 (1 μM) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.
- Dogne, Jean-Michel,Wouters, Johan,Rolin, Stephanie,Michaux, Catherine,Pochet, Lionel,Durant, Francois,Delarge, Jacques,Masereel, Bernard
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p. 669 - 680
(2007/10/03)
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- 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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