References of "Pirotte, Bernard"
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See detailAGE-RELATED MACULAR DEGENERATION (AMD): FROM METABOLOMICS APPROACH TO THE INHIBITION OF PDK AS A NEW THERAPEUTIC TARGET
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, September 09)

Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is ... [more ▼]

Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase inhibitors (PDK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease [less ▲]

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See detailNMR in the Pharmaceutical and Biomedical areas for identification and quantification of drugs and metabolomics applications
LAMBERT, Vincent ULg; Dufour, Gilles ULg; Chiap, Patrice ULg et al

Conference (2014, June 23)

Nuclear Magnetic Resonance (NMR) is probably, with mass spectrometry, the most powerful analytical tool for the structural determination of organic compounds. For a long time and due to technical ... [more ▼]

Nuclear Magnetic Resonance (NMR) is probably, with mass spectrometry, the most powerful analytical tool for the structural determination of organic compounds. For a long time and due to technical limitations, the main applications of NMR were focused on chemistry (organic, inorganic and medicinal chemistry) or biochemistry (i.e. proteins and proteins ligands analysis). Indeed, despite of very interesting potential in terms of structural information, reproducibility, specificity, quantification, NMR suffered of a lack of sensitivity and sometime of resolution in the case of complex mixture analysis in comparison with other technics. However, since several years, important technical improvements such as huge increase in sensitivity, hyphenation of NMR with LC system, automation and development of 2D and presaturation sequences have opened new putative applications for NMR, specifically in the pharmaceutical and biomedical areas. Then, beside the mass and chromatographic technics classically used for drug analysis, NMR represents an interesting and complementary tool for many applications. In this presentation, we will describe some NMR applications related to the pharma area. Starting from the identification of xenobiotic metabolites by coupling LC-SPE-NMR data with LC-MS/MS results, quantification of cyclodextrines in complex media, identification of illicit compounds, we will finish with our recent metabolomics NMR developments. [less ▲]

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See detailLIGAND-INDEPENDENT IDENTIFICATION OF ORPHAN GPCR ARRESTIN BINDING
Dupuis, Nadine ULg; Gilissen, Julie ULg; Derj, Anouar ULg et al

Poster (2014, June 05)

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See detailDesign and synthesis of high-affinity ligands of AMPA receptors and study of their Fluorine-18 radiolabeling
Deverdenne, François ULg; Goffin, Eric ULg; Plenevaux, Alain ULg et al

Poster (2014, June 05)

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the ... [more ▼]

The AMPA subtype of glutamatergic receptors is the main actor in the excitatory neurotransmission in the mammalian central nervous system. These receptors are involved in the expression and the maintenance of the long-term potentiation, a phenomenon closely linked to cognitive and memorization processes. Based on experimental data collected in recent years, the use of AMPA potentiators seems to be an interesting approach in the treatment of cognitive deficits (e.g. Alzheimer disease), schizophrenia or depression. Such AMPA signal potentiation could be mediated by positive allosteric modulators (PAMs) of the AMPA receptors, a class of compounds able to produce a fine signal tuning in the presence of the endogenous ligand in the synapse, providing less toxicity than direct agonists. With this approach, the laboratory of Medicinal Chemistry of Liège university developed many series of AMPA potentiators , among which 1,2,4-benzothiadiazine 1,1-dioxides (BTDs). In order to better understand the in vivo mapping of AMPA receptors and its evolution in neurological diseases, the present work aims at developing the design and the synthesis of BTDs positive allosteric modulators radiolabeled with a fluorine-18 atom. Based on previously synthesized series in this field, we investigate the synthesis of a new class of high-affinity AMPA potentiators characterized by the presence of a fluorine atom at selected positions on the structure of the AMPA potentiators. Thanks to in vitro pharmacological evaluations, we will further determine the best candidates for their fluorine-18 radiolabeling. [less ▲]

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See detailInhibition of PDH Kinase as a new therapeutic target for Age-related Macular Degeneration (AMD)
Arslan, Deniz ULg; Pirotte, Bernard ULg; De Tullio, Pascal ULg et al

Poster (2014, June)

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a ... [more ▼]

Metabolomics is one of the most recent technologies in the world of Omics sciences. It aims at studying metabolome, which is composed of small molecular weight organic molecules (called metabolites) of a cell, an organism or a biological system. This approach gives rise to a growing number of applications in many areas, such as biomarkers discovery, clinical studies, drug efficacy and toxicity evaluation, diagnostic tools, quality control. One of the most interesting features of metabolomics is its capability to extract biochemical information reflecting biological events and then to be a powerful tool in the knowledge of the aetiology of some pathologies. Indeed, it is clear that every disease could alter more or less drastically the metabolic profile of the patients. Then a metabolomics approach could highlight the biochemical pathways affected and could allow the identification of new putative therapeutic strategies or targets that could be useful in a new drug discovery strategy. As proteomics, metabolomics approach represents a new and powerful tool for Medicinal Chemistry. Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate DesHydrogenase Kinase inhibitors (PDHK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD disease. [less ▲]

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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 detailIdentification of chemical probes and signaling pathways for the orphan GPCR GPR27
Dupuis, Nadine ULg; Gilissen, Julie ULg; Pirotte, Bernard ULg et al

Poster (2013, June 06)

The largest family of membrane receptors is represented by G protein-coupled receptors (GPCRs), which are characterized by 7 transmembrane domains. Even if marketed drugs currently target only 10% of all ... [more ▼]

The largest family of membrane receptors is represented by G protein-coupled receptors (GPCRs), which are characterized by 7 transmembrane domains. Even if marketed drugs currently target only 10% of all GPCRs, they represent more than 30% of all small molecules based therapies. The physiological and pathophysiological role of a GPCR is defined by its expression pattern, signaling pathway and specific ligand[1]. GPCRs which have not yet been associated to a physiological ligand are called orphan GPCRs and represent ~100 of the ~370 human non-odorant GPCRs[2]. This project aims at identifying and developing pharmacological tools for GPR27 (SREB1), one of these orphan receptors. GPR27 has recently been shown to have a role in the regulation of insulin promoter activity and insulin secretion[3]. Nevertheless, the pharmacology of GPR27 remains elusive and the lack of appropriate pharmacological tools dramatically restricts the understanding of its function and its validation as a drug target. Thus, we plan to study its signaling pathway and to develop screening methods that will allow us to identify small molecules able to interact with GPR27. These are important steps toward understanding its function and evaluating GPR27 as a potential drug target, for instance in insulin-related metabolic disorders such as type II diabetes or in other pathologies where it might be involved. References 1) Wise, A., et al. (2002). Drug discovery today, 7, 235 2) Fredriksson, R., et al. (2003). Molecular pharmacology, 63, 1256 3) Ku, G. M., et al. (2012). PLoS genetics, 8, e1002449 [less ▲]

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See detailAge-related Macular Degeneration Study: A Metabolomics Approach
LAMBERT, Vincent ULg; Hansen, Sylvain ULg; Rousseau, Réjanne et al

Conference (2013, May 23)

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See detailSynthesis and pharmacological evaluation of 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas as novel thromboxane A2 receptor antagonists
Bambi-Nyanguile, Sylvie-Mireille; Hanson, Julien ULg; OOMS, Annie ULg et al

in European Journal of Medicinal Chemistry (2013), 65C

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See detailUnusual Amino Acids and Monofluoroacetate from Dichapetalum michelsonii (Umutambasha), a Toxic Plant from Rwanda
Esters, Virginie ULg; Karangwa, Charles; Tits, Monique ULg et al

in Planta Medica (2013), 79

In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly ... [more ▼]

In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly identified as Dichapetalum michelsonii Hauman. Conclusive evidence for a monofluoroacetate presence came from its isolation from the freeze-dried extract of stem bark. Three free unusual amino acids, named N-methyl-α-alanine, N-methyl-β-alanine, and 2,7-diaminooctan-1,8-dioic acid, described for the first time in a plant, and known trigonelline were also isolated from the stem bark of D. michelsonii. Structure elucidations were mainly achieved by spectroscopic methods (1H-NMR, 2D-NMR, MS) and by comparison with authentic references. These unusual amino acids were detected by a fast, reliable TLC analysis in all our batches of Umutambasha, suggesting that they could be used for identification purposes in case of human or livestock intoxications. Finally, EEG recordings and behavioural observations performed in mice suggested that the convulsive patterns produced by Umutambasha are the consequence of monofluoroacetate presence in D. michelsonii. [less ▲]

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See detailChemical probes and signaling pathways for the orphan GPCR GPR27
Dupuis, Nadine ULg; Gilissen, Julie ULg; Pirotte, Bernard ULg et al

Poster (2013, January 28)

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