References of "Goffin, Eric"
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See detailValidation analytique d'une méthode chromatographique destinée à rechercher et à identifier les opiacés naturels ou (semi) synthétiques
DUBOIS, Nathalie ULg; Counerotte, Stéphane ULg; Goffin, Eric ULg et al

in Annales de Biologie Clinique (2014), 72(2), 197-206

L’identification de la substance absorbée par un consommateur d’opiacés peut être problématique dans la mesure où il n’existe pas de biomarqueur spécifique pour toutes les molécules. Nous avons développé ... [more ▼]

L’identification de la substance absorbée par un consommateur d’opiacés peut être problématique dans la mesure où il n’existe pas de biomarqueur spécifique pour toutes les molécules. Nous avons développé une technique de chromatographie liquide ultra-haute pression couplée à un spectromètre de masse en tandem qui permet l’identification et le dosage de 25 opiacés dans le plasma. La préparation de l’échantillon consiste en une extraction en phase solide sur colonnes Oasis ® MCX (Waters). La méthode a été validée selon les critères préconisés par la FDA, complètement pour 21 substances et avec quelques réserves pour les 4 produits restants. Cette méthode a été appliquée à 80 patients traités au CHU de Liège pour lesquels la recherche d’opiacés était positive. L’identification du produit consommé a été effective dans 86 % des cas. [less ▲]

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See detailSynthesis, Pharmacological and Structural Characterization, and Thermodynamic Aspects of GluA2-Positive Allosteric Modulators with a 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Scaffold
Nørholm, Ann-Beth; Francotte, Pierre ULg; Olsen, Lars et al

in Journal of Medicinal Chemistry (2013), 56(21), 87368745

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 ... [more ▼]

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 Kd 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. [less ▲]

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See detailDevelopment of Thiophenic Analogues of Benzothiadiazine Dioxides as New Powerful Potentiators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid (AMPA) Receptors
Francotte, Pierre ULg; Goffin, Eric ULg; Fraikin, Pierre et al

in Journal of Medicinal Chemistry (2013), 56(20), 7838-7850

On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the ... [more ▼]

On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low as 0.3 mg/kg. This study validates the interest of the isosteric replacement of the benzene or pyridine nuclei by the thiophene nucleus in the ring-fused thiadiazine dioxides class of AMPA potentiators. [less ▲]

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See detailTriphenylphosphonium salts of 1,2,4-benzothiadiazine 1,1-dioxides related to diazoxide targeting mitochondrial ATP-sensitive potassium channels
Constant-Urban, C.; Charif, M.; Goffin, Eric ULg et al

in Bioorganic & Medicinal Chemistry Letters (2013), 23

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See detailAMPA receptor positive allosteric modulators: a patent review
Pirotte, Bernard ULg; Francotte, Pierre ULg; Goffin, Eric ULg et al

in Expert Opinion on Therapeutic Patents (2013), 23

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See detailN-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.
Goffin, Eric ULg; Lamoral-Theys, Delphine; Tajeddine, Nicolas et al

in European Journal of Medicinal Chemistry (2012), 54

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three ... [more ▼]

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action. [less ▲]

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See detailNew Fluorinated 1,2,4-Benzothiadiazine 1,1-Dioxides: Discovery of an Orally Active Cognitive Enhancer Acting through Potentiation of the 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors
Francotte, Pierre ULg; Goffin, Eric ULg; Fraikin, Pierre ULg et al

in Journal of Medicinal Chemistry (2010), 53

In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In ... [more ▼]

In the search of a potent cognitive enhancer, a series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as positive allosteric modulators of the AMPA receptors. In the present work, we focused our efforts on the insertion of mono- or polyfluoro- substituted alkyl chains at the 4-position of the thiadiazine ring in an attempt to enhance the pharmacokinetic behavior of previously described compounds. Among all the described compounds, 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, 12b, was shown to exert a strong activity on AMPA receptors in vitro and a marked cognitive-enhancing effect in vivo after oral administration to Wistar rats. Considering its in vivo activity, the metabolic degradation of 12b was studied and compared to that of its nonfluorinated analogue 9b. Taken together, results of this study clearly validated the positive impact of the fluorine atom on the alkyl chain at the 4-position of benzothiadiazine dioxides on activity and metabolic stability. [less ▲]

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See detailDesign, synthesis, and pharmacology of novel 7-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors
Francotte, Pierre ULg; De Tullio, Pascal ULg; Goffin, Eric ULg et al

in Journal of Medicinal Chemistry (2007), 50(13), 3153-3157

A series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as potentiators of AMPA receptors. Attention was paid to the impact of the substituent introduced at the ... [more ▼]

A series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been synthesized and evaluated as potentiators of AMPA receptors. Attention was paid to the impact of the substituent introduced at the 7-position of the heterocycle. The biological evaluation was achieved by measuring the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most potent compound, 4-ethyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (12a) was found to be active in an object recognition test in rats demonstrating cognition enhancing effects in vivo after oral administration. [less ▲]

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