References of "Francotte, Pierre"
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See detailCoupling of Liquid Chromatography/Tandem Mass Spectrometry and Liquid Chromatography/Solid-Phase Extraction/NMR Techniques for the Structural Identification of Metabolites following In Vitro Biotransformation of SUR1-Selective ATP-Sensitive Potassium Channel Openers
Gillotin, F.; Chiap, Patrice ULg; Frederich, Michel ULg et al

in Drug Metabolism and Disposition : The Biological Fate of Chemicals (2010), 38(2), 232-240

SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity and ... [more ▼]

SUR1-selective ATP-sensitive potassium channel openers (PCOs) have been shown to be of clinical value for the treatment of several metabolic disorders, including type I and type II diabetes, obesity and hyperinsulinemia. Taking into account these promising therapeutic benefits, different series of 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides structurally related to diazoxide were developed. In view of the lead optimisation process of the series, knowledge of ADMET parameters, and more particularly the metabolic fate of these compounds, is a fundamental requirement. For such a purpose, two selected promising compounds (BPDZ 73 and BPDZ 157) were incubated in the presence of phenobarbital-induced rat liver microsomes to produce expected mammal in vivo phase I metabolites. The resulting major metabolites were then analysed by both MS and NMR in order to completely elucidate their chemical structures. The two compounds were also further incubated in the presence of non-treated rats and human microsomes in order to compare the metabolic profiles. In the present study, the combined use of an exact mass LC-MS/MS platform and a LC-SPE-NMR system allowed the clarification of some unresolved structural assessments in the accurate chemical structure elucidation process of the selected PCOs drugs. These results greatly help the optimization of the lead compounds. [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 biological evaluation of cognitive enhancers acting through the potentiation of the AMPA receptors
Francotte, Pierre ULg

Doctoral thesis (2008)

Alzheimer’s disease (AD) represents one of the greatest health problems in industrialized countries considering the ageing population. Only four drugs are currently approved for the treatment of this ... [more ▼]

Alzheimer’s disease (AD) represents one of the greatest health problems in industrialized countries considering the ageing population. Only four drugs are currently approved for the treatment of this disease. As these drugs are characterized with a limited time efficacy, it has become urgent to develop additional innovative AD treatments. Amongst the approaches that are actively investigated, the one consisting in potentiating a subclass of glutamate receptors appears attractive. This well advanced pharmacological approach includes three major classes of compounds amongst which appear the benzothiadiazine 1,1-dioxides. The present thesis is a pursuit of the preliminary efforts that were published in 1998 and 2001 by our team. Based on promising in vitro results obtained with the lead compound 59, pharmacomodulations around 59’s structure have been achieved in order to enhance its in vivo activity and to optimize its pharmacokinetic parameters. First efforts were devoted to exploratory synthesis where attention was paid to the impact of the substituent introduced at the 7-position. Moreover, some pyridothiadiazine dioxides as well as thienothiadiazine dioxides were prepared. The most important part of our pharmacomodulations was focused on the thiadiazine ring system. Considering that the poor in vivo results obtained with 59 could be due to a metabolic weakness of the latter, the introduction of fluorine atoms was tempted as a lead optimization strategy. This approach was successful, since it led to the synthesis of 95b which was selected for further pharmacological evaluations. This new lead compound was shown to exert significant cognitive-enhancing effects in vivo after oral administration to Wistar rats. Moreover, the study of the metabolic degradation of 95b allowed the assessment of the starting hypothesis that had dictated the pharmacomodulation’s philosophy. Finally, additional exploratory pharmacomodulations were achieved notably leading to the preparation of a quinazolinone series and 1,4-benzothiazine compounds. This research allowed to significantly improve the pharmacokinetic profile of our series and led to the identification of 95b as a new lead compound. However, many pharmacomodulations remain to be explored. The data collected during this thesis are appealing further studies. Efforts in the near future should lead to the design of novel drug candidates among which a future innovative AD treatment could emerge. [less ▲]

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See detailSynthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators.
Francotte, Pierre ULg; De Tullio, Pascal ULg; Podona, Tchao et al

in Bioorganic & Medicinal Chemistry (2008), 16(23), 9948-56

Taking into account structure-activity relationships obtained with our previous series, new diversely substituted 1,2,4-pyridothiadiazine 1,1-dioxides were designed to obtain novel AMPA potentiators. The ... [more ▼]

Taking into account structure-activity relationships obtained with our previous series, new diversely substituted 1,2,4-pyridothiadiazine 1,1-dioxides were designed to obtain novel AMPA potentiators. The aim of this work was focused on the improvement of lipophilicity, which is well known as a critical parameter to obtain in vivo active central nervous system agents. For this purpose, two positions on the pyridine ring were privileged to insert selected groups. Among the synthesized compounds emerged 7-chloro-4-ethyl-3,4-dihydro-2H-pyrido[2,3-e]-[1,2,4]-thiadiazine 1,1-dioxide (12d), which was evaluated in two memory tests in Wistar rats and showed cognition enhancing effects after intraperitoneal injection at doses as low as 0.3mg/kg. [less ▲]

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See detailAChE Inhibitors and their Clinical Assessment
Francotte, Pierre ULg; De Tullio, Pascal ULg; Pirotte, Bernard ULg

in Protein Misfolding in Neurodegenerative Diseases: Mechanisms and Therapeutic Strategies (2007)

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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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See detailCholinergic Transmission and Acetylcholine release enhancers
Francotte, Pierre ULg; De Tullio, Pascal ULg; Pirotte, Bernard ULg

in Protein Misfolding in neuro degenerative Diseases : Mechanisms and Therapeutic Strategies (2007)

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See detailNovel dipyrazoles acting as glutamate modulators
Francotte, Pierre ULg; De Tullio, Pascal ULg; Pirotte, Bernard ULg

in Expert Opinion on Therapeutic Patents (2007), 17(12), 1489-1493

Knowing the potential therapeutic interest of AMPA potentiation, patents have been published for 15 years relating the discovery of novel compounds able to allosterically bind to the AMPA receptors and ... [more ▼]

Knowing the potential therapeutic interest of AMPA potentiation, patents have been published for 15 years relating the discovery of novel compounds able to allosterically bind to the AMPA receptors and leading to a potentiation of the AMPA signals. Besides this classical approach, a new target for the medicinal chemist has been defined due to the recent findings describing the modulation of AMPA receptors by neuronal proteins, and has led to the design of dipyrazole compounds by Aventis. These new dipyrazole derivatives may be considered as `indirect AMPApams', constituting a new pharmacological class. Based on their in vitro activity, it is probable that these compounds could be of therapeutic value for the treatment of cognitive disorders, schizophrenia or depression. [less ▲]

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