Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators

被引：24

作者：

Francotte, Pierre ^{[1
]}

de Tullio, Pascal ^{[1
]}

Podona, Tchao ^{[1
]}

Diouf, Ousmane ^{[1
]}

Fraikin, Pierre ^{[1
]}

Lestage, Pierre ^{[2
]}

Danober, Laurence ^{[2
]}

Thomas, Jean-Yves ^{[2
]}

Caignard, Daniel-Henri ^{[2
]}

Pirotte, Bernard ^{[1
]}

机构：

[1] Univ Liege, Med Chem Lab, Drug Res Ctr, B-4000 Liege, Belgium

[2] Inst Rech Servier, F-78290 Croissy Sur Seine, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 23期

关键词：

AMPA potentiator; Allosteric modulation; Cognitive enhancer;

D O I：

10.1016/j.bmc.2008.10.036

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-pyrido[2,3-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 0.3 mg/kg. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：9948 / 9956

页数：9

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