Reference : Design, synthesis and biological evaluation of cognitive enhancers acting through the...
Dissertations and theses : Doctoral thesis
Human health sciences : Pharmacy, pharmacology & toxicology
Physical, chemical, mathematical & earth Sciences : Chemistry
Design, synthesis and biological evaluation of cognitive enhancers acting through the potentiation of the AMPA receptors
Francotte, Pierre mailto [Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique >]
Université de Liège, ​Liège, ​​Belgique
Docteur en Sc. Biomédicales et Pharmaceutiques
Pirotte, Bernard mailto
De Tullio, Pascal mailto
Seutin, Vincent mailto
Demonceau, Albert mailto
Lejeune, Robert mailto
Lambert, Didier
Krogsgaard Larsen, Povl
[en] cognitive enhancer ; AMPA potentiator ; Alzheimer's disease
[en] 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.
Centre Interfacultaire de Recherche du Médicament

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