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.
References
Nov 1, 1988·Behavioural Brain Research·A Ennaceur, J Delacour
Apr 1, 1972·Journal of Medicinal Chemistry·J G Topliss, M D Yudis
Dec 24, 1971·Brain Research·K K Skrede, R H Westgaard
Sep 20, 1968·Psychopharmacologia·S Irwin
Jun 4, 1966·Nature·C Yamamoto, H McIlwain
Nov 15, 1993·European Journal of Pharmacology·J C RandleJ M Lepagnol
Jan 7, 1993·Nature·T V Bliss, G L Collingridge
Jul 31, 1998·Journal of Medicinal Chemistry·B PirotteM Spedding
Mar 12, 2002·Bioorganic & Medicinal Chemistry·Dean PhillipsA Richard Chamberlin
May 31, 2002·Journal of Medicinal Chemistry·Daniela BraghiroliMario Baraldi
May 13, 2003·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Roberto Malinow
May 1, 1964·Journal of Medicinal Chemistry·J G TOPLISSF E ROTH
Jan 27, 2005·Psychopharmacology·Mark D Black
Jan 27, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Agnès GruartJosé M Delgado-García
Jun 8, 2007·Journal of Medicinal Chemistry·Pierre FrancotteBernard Pirotte
Jun 24, 2008·Journal of Medicinal Chemistry·William K Hagmann
Nov 5, 2008·Bioorganic & Medicinal Chemistry·Pierre FrancotteBernard Pirotte
Citations
Oct 5, 2013·Journal of Medicinal Chemistry·Pierre FrancottePascal de Tullio
Oct 18, 2013·Journal of Medicinal Chemistry·Ann-Beth NørholmJette S Kastrup
Jan 16, 2016·ACS Chemical Neuroscience·Anja Probst LarsenJette Sandholm Kastrup
May 26, 2011·Neuroscience Research·Sophie MourlevatBrian Paul Lockhart
Nov 19, 2015·ACS Chemical Neuroscience·Cinzia CittiMichele Zoli
Feb 15, 2013·Expert Opinion on Therapeutic Patents·Bernard PirottePascal de Tullio
Sep 9, 2017·Chemistry : a European Journal·Bálint PethőZoltán Novák
Nov 11, 2017·Chemical Communications : Chem Comm·Fatemeh HaghighiAli Khalafi-Nezhad
Aug 11, 2018·Organic & Biomolecular Chemistry·Hui WangXiang-Guo Hu
Feb 12, 2019·ChemMedChem·Alexandra Manos-TurveyChristian Lemaire
Jan 3, 2013·ChemMedChem·Haijun ChenJia Zhou
Apr 1, 2017·Molecular Pharmacology·Anja Probst LarsenChristophe Mulle
Nov 12, 2019·Organic & Biomolecular Chemistry·Suo ChenXiang-Guo Hu
Apr 26, 2013·Beilstein Journal of Organic Chemistry·Krishna C Majumdar, Sintu Ganai
Jun 25, 2016·Beilstein Journal of Organic Chemistry·Long-Yi XiXiao-Qi Yu
Sep 12, 2015·Angewandte Chemie·Haiqing LuoJianbo Wang
Nov 18, 2020·Angewandte Chemie·Ryan T McGuireMark Stradiotto
Jul 10, 2021·ACS Chemical Neuroscience·Koffi Sénam EtsèPierre Francotte
Jan 12, 2012·ACS Medicinal Chemistry Letters·Umberto M BattistiLuigino Troisi
Nov 7, 2014·Journal of Medicinal Chemistry·Pierre FrancotteBernard Pirotte
Nov 25, 2014·Journal of Chemical Information and Modeling·Ann-Beth NørholmChris Oostenbrink
Dec 20, 2017·Journal of Medicinal Chemistry·Eric GoffinPierre Francotte
Mar 21, 2019·ACS Medicinal Chemistry Letters·Simone BrogiStefania Butini
Jun 13, 2015·Journal of the American Chemical Society·Andrew T Brusoe, John F Hartwig
Sep 23, 2021·Organic & Biomolecular Chemistry·Yuqi ZhangZhuo Zeng