Discovery of the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine scaffold as a novel, potent and selective GABAA α5 inverse agonist series

被引：28

作者：

Achermann, Guido ^{[1
]}

Ballard, Theresa M. ^{[2
]}

Blasco, Francesca ^{[3
]}

Broutin, Pierre-Emmanuel ^{[1
]}

Buettelmann, Bernd ^{[1
]}

Fischer, Holger ^{[1
]}

Graf, Martin ^{[4
]}

Hernandez, Maria-Clemencia ^{[2
]}

Hilty, Peter ^{[1
]}

Knoflach, Frederic ^{[2
]}

Koblet, Andreas ^{[1
]}

Knust, Henner ^{[1
]}

Kurt, Anke ^{[1
]}

Martin, James R. ^{[2
]}

Masciadri, Raffaello ^{[1
]}

Porter, Richard H. P. ^{[2
]}

Stadler, Heinz ^{[1
]}

Thomas, Andrew W. ^{[1
]}

Trube, Gerhard ^{[2
]}

Wichmann, Juergen ^{[1
]}

机构：

[1] F Hoffmann La Roche Ltd, Pharmaceut Res Basel, Discovery Chem, CH-4070 Basel, Switzerland

[2] F Hoffmann La Roche Ltd, Pharmaceut Res Basel, CNS Dis Biol Area, CH-4070 Basel, Switzerland

[3] F Hoffmann La Roche Ltd, Pharmaceut Res Basel, NonClin Safety, CH-4070 Basel, Switzerland

[4] F Hoffmann La Roche Ltd, Pharmaceut Res Basel, Discovery Technnol, CH-4070 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 19期

关键词：

GABA(A) receptor; Benzodiazepines; Cognition; Imidazole; Triazole; Medicinal chemistry; AMINOBUTYRIC ACID(A) RECEPTORS; BENZODIAZEPINE SITE; ALZHEIMERS-DISEASE; HIGH-AFFINITY; COGNITION; PHARMACOLOGY; SUBTYPES; LIGAND; PERFORMANCE; METABOLISM;

D O I：

10.1016/j.bmcl.2009.07.153

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Through iterative design cycles we have discovered a number of novel new classes where the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][ 1,4]benzodiazepine was deemed the most promising GABA(A) alpha 5 inverse agonist class with potential for cognitive enhancement. This class combines a modest subtype binding selectivity with inverse agonism and has the most favourable molecular properties for further lead optimisation towards a central nervous system (CNS) acting medicine. (C) 2009 Published by Elsevier Ltd.

引用

页码：5746 / 5752

页数：7

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