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.
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.
Francotte
Pierre
P
Centre Interfacultaire de Recherche du Médicament, Laboratoire de Chimie Pharmaceutique, Université de Liège, Belgium. Pierre.Francotte@ulg.ac.be
Goffin
Eric
E
Fraikin
Pierre
P
Lestage
Pierre
P
Van Heugen
Jean-Claude
JC
Gillotin
Florian
F
Danober
Laurence
L
Thomas
Jean-Yves
JY
Chiap
Patrice
P
Caignard
Daniel-Henri
DH
Pirotte
Bernard
B
de Tullio
Pascal
P
D000284:Administration, Oral; D000494:Allosteric Regulation; D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018697:Nootropic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000502:physiology*; D021641:Recognition, Psychology / Q000187:drug effects; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
C547951:7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D018683:Excitatory Amino Acid Agents; D018697:Nootropic Agents; D018091:Receptors, AMPA