References of "Delarge, J"
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See detailSynthesis and pharmacological effects of opened analogues of benzothiadiazine 1,1-dioxides with sulfonylurea moieties on diuresis and glycemia
Khelili, S.; Bouider, N.; Delarge, J. et al

Poster (2005, May)

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See detailPyridinic sulfonamide derivatives, method of production and use thereof
Delarge, J.; Pirotte, Bernard ULg; Dogné, J. M. et al

Patent (2003)

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See detailEvaluation of classical NSAIDS on COX-1 and COX-2 purifies enzymes and prognosis of their effects on physiological responses.
De Leval, X.; Henrotin, Yves ULg; Masereel, B. et al

in Fundamental & Clinical Pharmacology (2003), 14

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See detailPharmacological evaluation of the novel thromboxane modulator BM-567 (II/II). Effects of BM-567 on osteogenic sarcoma-cell-induced platelet aggregation
De Leval, X.; Benoit, V.; Delarge, J. et al

in Prostaglandins, Leukotrienes, and Essential Fatty Acids (2003)

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See detailNew pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors
Liégeois, Jean-François ULg; Eyrolles, L.; Ellenbroek, B. A. et al

in Journal of Medicinal Chemistry (2002), 45(23), 5136-5149

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol ... [more ▼]

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K-i > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D-4.2 and 5-HT2A receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-metbylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo [3.2.1] octane derivatives (23, 38) involved a slight reduction of the affinity at D-4.2 and 5-HT2A receptors while the affinity at D-2L receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D-4.2 receptors but some of these molecules (24, 25, 41) presented a significant 5-HT2A binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D-4.2 and 5-HT2A affinity (K-i = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties. [less ▲]

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See detailMinimal effects of JL 13, a pyridobenzoxazepine derivative with an antipsychotic potential, on circulating prolactin levels in male rats
Liégeois, Jean-François ULg; Bruhwyler, J.; Hendrick, J. C. et al

in Neuroscience Letters (2002), 319(1), 49-52

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal ... [more ▼]

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal injection in gentled male rats in comparison with clozapine and haloperidol. A total of 30 or 150 min after administration, whole blood was collected for preparing serum samples. Prolactin was quantified by radioimmunoassay method. At 30 min, JL 13 like clozapine, increased prolactin concentration only at the higher dose (30 mg/kg) while haloperidol at both tested doses induced a dramatic increase of prolactin concentration. At 150 min after injection, only haloperidol (0.3 mg/kg) significantly increased serum prolactin level. This minimal effect on prolactinemia reinforces the similarity of clozapine and JL 13 regarding the atypical antipsychotic profile. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. [less ▲]

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See detailAdvances in the field of COX-2 inhibition
De Leval, X.; Julémont, F.; Delarge, J. et al

in Expert Opinion on Therapeutic Patents (2002), 12

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See detailNew trends in dual 5-LOX/COX inhibition
De Leval, X.; Julémont, F.; Delarge, J. et al

in Current Medicinal Chemistry (2002), 9

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See detailEvaluation d’inhibiteurs de cyclooxygénases et d’antagonistes du TXA2 sur la migration des cellules endothéliales in vitro
Lux, C.; Delarge, J.; De Leval, X. et al

Poster (2001, June 01)

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See detailSynthèse et évaluation enzymatique de nouvelles coumarines en tant qu’inhibiteurs de thrombine
Pochet, L.; Doucet, C.; Pirotte, Bernard ULg et al

Poster (2001, June 01)

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See detailSynthèse et évaluation pharmacologique d’un méthanesulfonamide pyridinique apparenté à l’acide niflumique
Julemont, F.; De Leval, X.; Neven, P. et al

Poster (2001, June 01)

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See detailEffects of thromboxane A2 receptor antagonists and COX inhibitors on osteogenic sarcome cell-induced platelet aggregation
De Leval, X.; Delarge, J.; Neven, P. et al

Poster (2001, June 01)

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See detailSynthesis and pharmacological evaluation of pyridinic methanesulfonamides as potential COX-2 inhibitors
Julémont, F.; de Leval, X.; Neven, P. et al

Conference (2001, May 24)

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See detailSynthesis and pharmacological evaluation of pyridinic methanesulfonamides as potential COX-2 inhibitors
Julemont, F.; De Leval, X.; Neven, P. et al

Conference (2001, May)

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See detailElectrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-Like Analogues
Mouithys-Mickalad, Ange ULg; Kauffmann, J. M.; Petit, C. et al

in Journal of Medicinal Chemistry (2001), 44(5), 769-76

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9 ... [more ▼]

The chemical modification of clozapine (1) has permitted the finding of new analogues, e.g., olanzapine (2), quetiapine (3), 5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine fumarate (9), with a clinical or psychopharmacological profile similar to that of clozapine. However, when developing new derivatives, the designers are discouraged by the development of clozapine-induced agranulocytosis. Different researchers have raised the role played by the oxidizability of the molecule in such a deleterious effect. In the present paper, we examined the oxidation profile (direct scavenging abilities, efficacy in inhibiting lipid peroxidation, and electrooxidation potential) of newly developed methoxy and trifluoromethylsulfonyloxy analogues related to clozapine, some of them being described as putative antipsychotic. The oxazepine derivative 7, unlike the other diazepine derivatives (6, 10--12), was not readily oxidized. Using a statistical predictive model for hematotoxicity previously described, 7 was found in the cluster of potentially nontoxic compounds while diazepine derivatives 6 and 10-12 were classified as potentially toxic compounds. Among these original compounds, 7, which presents a preclinical clozapine-like profile and a low sensitivity to oxidation, could be a promising antipsychotic candidate with low side effects. Considering the tricyclic derivatives examined so far, some elements of structure-oxidation relationship (SOR) might be pointed out. Regarding the nature of the tricyclic ring substituent, from the most to the least sensitive to oxidation, the sequence was as follows: HO > Cl > CH(3)O > CF(3)SO(2)O. The nature of the tricyclic ring influenced also the sensitivity to oxidation; the diazepine moiety appeared to be the most reactive ring compared to oxa- and thiazepine congeners. These parameters could be advantageously integrated in the early design of new safer clozapine-like analogues. [less ▲]

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See detailConception, synthèse et évaluation pharmacologique d’analogues pyridiniques du Nimésulide en tant qu’inhibiteurs potentiels des cyclooxygénases
Julémont, Fabien; De Leval, X.; Neven, P. et al

Poster (2001, January 26)

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See detailEvaluation of classical NSAIDS and COX-2 selective inhibitors on purified ovine enzymes and human whole blood
de Leval, X; Dogne, JM; Delarge, J et al

in Clinical Rheumatology (2001), 20

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See detailIn vitro effects of aceclofenac and its metabolites on the production by chondrocytes of inflammatory mediators.
Henrotin, Yves ULg; de Leval, X.; Mathy, Marianne ULg et al

in Inflammation Research (2001), 50(8), 391-9

OBJECTIVES: To investigate the mechanisms of action underlying the anti-inflammatory action of aceclofenac in vivo, we studied in vitro the effect of aceclofenac and its main metabolite, 4 ... [more ▼]

OBJECTIVES: To investigate the mechanisms of action underlying the anti-inflammatory action of aceclofenac in vivo, we studied in vitro the effect of aceclofenac and its main metabolite, 4'-hydroxyaceclofenac, in comparison with diclofenac, another metabolite, on cyclooxygenases activity as well as interleukin-1beta, -6 and -8, nitric oxide, and prostaglandin E2 production by human osteoarthritic and normal articular chondrocytes. METHODS: Enzymatically isolated human chondrocytes were cultured for 72 h in the absence or presence of interleukin-1beta (IL-1beta) or lipopolysacharride (LPS) and with or without increased amounts (1 to 30 microM) of aceclofenac or metabolites. The production of different cytokines was measured by Enzyme Amplified Sensitivity Immunoassays (EASIA). Prostaglandin E2 was quantified by a specific radioimmunoassay. Nitrite and nitrate concentrations in the culture supernatants were determined by spectrophotometric method based upon the Griess reaction. Cyclooxygenase-2, inducible NO synthase and IL-1beta gene expression were quantified by reverse transcription of mRNA followed by real time and quantitative polymerase chain reaction. Finally, cyclooxygenase inhibitory potency of the drugs was also tested in both a cell-free system using purified ovine cyclooxygenase-1 and -2 (COX-1 and COX-2) and at a cellular level using human whole blood assay. RESULTS: We have demonstrated that aceclofenac, 4'-hydroxyaceclofenac and diclofenac significantly decreased interleukin-6 production at concentrations ranged among 1 to 30 microM and fully blocked prostaglandin E2 synthesis by IL-1beta- or LPS-stimulated human chondrocytes. Aceclofenac and diclofenac had no effect on interleukin-8 production while 4'-hydroxyaceclofenac slightly decreased this parameter at the highest dose (30 microM). Aceclofenac was without effect on IL-1beta- or LPS-stimulated nitric oxide production. At 30 microM, 4'-hydroxyaceclofenac inhibited both IL-1beta or LPS-stimulated nitric oxide production while diclofenac inhibited only the LPS-stimulated production. Finally, at 30 microM, the three drugs significantly decreased IL-1beta mRNA. In the whole blood test, aceclofenac and 4'-hydroxyaceclofenac weakly inhibited COX-1 with IC50 values superior to 100 microM, but decreased by 50% COX-2 activity at the concentration of 0.77 and 36 microM, respectively. Diclofenac strongly inhibited both COX-1 and COX-2 with IC50 values of 0.6 and 0.04 microM, respectively. On the other hand, aceclofenac and diclofenac weakly inhibited purified ovine cyclooxygenases with IC50 values superior to 100 microM, whereas 4'-hydroxyaceclofenac was without effect. CONCLUSIONS: These results suggest that aceclofenac actions are multifactorial and that metabolites could contribute to its anti-inflammatory actions. [less ▲]

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