Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators |
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Authors: | Francotte Pierre de Tullio Pascal Podona Tchao Diouf Ousmane Fraikin Pierre Lestage Pierre Danober Laurence Thomas Jean-Yves Caignard Daniel-Henri Pirotte Bernard |
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Institution: | Drug Research Center, Laboratory of Medicinal Chemistry, University of Liège, Av. de l'H?pital, 1, B36, 4000 Liège, Belgium. Pierre.Francotte@ulg.ac.be |
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Abstract: | Taking into account structure-activity relationships obtained with our previous series, new diversely substituted 1,2,4-pyridothiadiazine 1,1-dioxides were designed to obtain novel AMPA potentiators. The aim of this work was focused on the improvement of lipophilicity, which is well known as a critical parameter to obtain in vivo active central nervous system agents. For this purpose, two positions on the pyridine ring were privileged to insert selected groups. Among the synthesized compounds emerged 7-chloro-4-ethyl-3,4-dihydro-2H-pyrido2,3-e]-1,2,4]-thiadiazine 1,1-dioxide (12d), which was evaluated in two memory tests in Wistar rats and showed cognition enhancing effects after intraperitoneal injection at doses as low as 0.3mg/kg. |
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