Reference : New Fluorinated 1,2,4-Benzothiadiazine 1,1-Dioxides: Discovery of an Orally Active Cogni...
Scientific journals : Article
Human health sciences : Pharmacy, pharmacology & toxicology
http://hdl.handle.net/2268/33867
New 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
English
Francotte, Pierre mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Goffin, Eric mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Fraikin, Pierre mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Lestage, Pierre [ > > ]
Van Heugen, Jean-Claude mailto [Université de Liège - ULg > > Chimie médicale >]
Gillotin, Florian [ > > ]
Danober, Laurence [ > > ]
Thomas, Jean-Yves [ > > ]
Chiap, Patrice mailto [Université de Liège - ULg > Département de pharmacie > Département de pharmacie >]
Caignard, Daniel-Henri [ > > ]
Pirotte, Bernard mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
De Tullio, Pascal mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
2010
Journal of Medicinal Chemistry
American Chemical Society
53
1700-1711
Yes (verified by ORBi)
International
0022-2623
1520-4804
Washington
DC
[en] cognitive enhancer ; AMPA potentiator ; Alzheimer's disease
[en] 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.
Researchers ; Professionals
http://hdl.handle.net/2268/33867
10.1021/jm901495t

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