References of "Pirotte, Bernard"
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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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See detailSynthesis and characterization of Zn(1-x)NixAl2O4 spinels as a new heterogeneous catalyst of Biginelli's reaction
Akika, F.-Z.; Kihal, N.; Habila, T. et al

in Bulletin of the Korean Chemical Society [= BKCS] (2013), 34

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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 detailN-tert-butyl-N'-[5-cyano-2-(4-methylphenoxy)phenylsulfonyl]urea, a new TXA₂ receptor antagonist
Bambi Nyanguile, S.M.; Mangwala Kimpende, P.; Pirotte, Bernard ULg et al

in Acta Crystallographica Section C-Crystal Structure Communications (2013), 69

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See detailEffects of diazoxide, benzothiadiazine and benzopyrane derivatives on mitochondrial proton and electron leaks of cardiomyocytes (H9C2 cell line).
Mouithys-Mickalad, Ange ULg; Ceusters, Justine ULg; Charef, M et al

Poster (2013)

Background: Mitochondria are double membrane- organelles that play a central role in cellular metabolism, calcium homeostasis and redox signaling. They have been also considered as main producers of ... [more ▼]

Background: Mitochondria are double membrane- organelles that play a central role in cellular metabolism, calcium homeostasis and redox signaling. They have been also considered as main producers of adenosine triphosphate (ATP) and reactive oxygen species (ROS). In many cancer cells those organelles become dysfunctional leading to a shift of energy metabolism from oxidative phosphorylation to active glycolysis and an increase of ROS generation. According to Warberg’ theory, cancer damage might occur at the mitochondrial level, affecting tiny structures within each cell implicated in the energy production through ATP. New insight is that mitochondria might be a good therapeutic target for metabolic syndromes, ischemia/reperfusion injury and organs transplantation. Therefore, search for novel molecules able to keep mitochondria functional are of relevant interest. Methodology: Cardiomyocytes (H9C2 cells) were from ATCC (USA) and grown till confluence. The basal cellular respiratory rate, proton and electron leaks as well as ATP production were measured with the High Resolution Oxygraphy (Oroboros, Austria). All compounds: diazoxide (DIAZ), diazoxide –related analogs (1: BPDZ-259, 2: BPDZ-444), and benzopyran derivatives (3: BPDZ-490, 4: BPDZ-711) were tested at final concentration of 10-5 M, except when specified and compared to control samples (cells with or without DMSO). Results and conclusion: The basal respiratory rate of H9C2 cells (5x106/mL) was changed depending on the chemical structure of the tested compounds: e.g. compound 3 strongly enhanced the routine respiration, while 4 displayed a marked lowering effect. In contrast, the addition of similar concentration of benzothiadiazin derivatives (1, 2) had no effect on routine respiration but also on the other respiratory parameters such as oligomycin-induced leak and ATP production. Similar profile was obtained with the reference molecule: diazoxide. Overall, our findings indicate that both diazoxide-like analogues (1 and 2) and diazoxide were without significant effect on basal respiration, ATP production, even on maximal respiration. Interestingly, two derivatives show opposite effects: compound 3 behaves as a uncoupling agent and the other one (4) exhibits a real lowering effect on respiration but that was reversible. The latter effect might be of interest if this kind of molecules could be used for further use as an agent for organ conservation during transplantation. Our results also demonstrate that diazoxide, a well-known Mito-KATP opener, did not exert its effect beside of clinical situation like ischemia/reperfusion injury. [less ▲]

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See detailHeterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A4
Hanson, Julien ULg; Ferreiros, Nerea; Pirotte, Bernard ULg et al

in Biochemical Pharmacology (2013), 85

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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 detailDevelopment of original 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas as thromboxane A2 receptor antagonists
Bambi Nyanguile, Sylvie-Mireille ULg; Hanson, Julien ULg; Dogné, Jean-Michel et al

Poster (2012, August)

A series of novel 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized. The newly synthesized compounds were tested in vitro and ex vivo as thromboxane A2 receptor antagonists. Some of the ... [more ▼]

A series of novel 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized. The newly synthesized compounds were tested in vitro and ex vivo as thromboxane A2 receptor antagonists. Some of the test compounds showed potent thromboxane A2 receptor antagonist activity. Three compounds (7h, 8h and 8e) were identified as leads for further pharmacological and toxicological studies. [less ▲]

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