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

Abstract

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.