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

Journal of Medicinal Chemistry
Pierre FrancottePascal de Tullio

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.

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Citations

Feb 15, 2013·Expert Opinion on Therapeutic Patents·Bernard PirottePascal de Tullio
Nov 11, 2017·Chemical Communications : Chem Comm·Fatemeh HaghighiAli Khalafi-Nezhad
Apr 1, 2017·Molecular Pharmacology·Anja Probst LarsenChristophe Mulle
Jun 25, 2016·Beilstein Journal of Organic Chemistry·Long-Yi XiXiao-Qi Yu
Nov 18, 2020·Angewandte Chemie·Ryan T McGuireMark Stradiotto
Jan 12, 2012·ACS Medicinal Chemistry Letters·Umberto M BattistiLuigino Troisi
Jun 13, 2015·Journal of the American Chemical Society·Andrew T Brusoe, John F Hartwig
Sep 23, 2021·Organic & Biomolecular Chemistry·Yuqi ZhangZhuo Zeng

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