Aminothiazoles as γ-secretase modulators

被引：19
|
作者：
Luebbers, Thomas [1 ]
Flohr, Alexander [1 ]
Jolidon, Synese [1 ]
David-Pierson, Pascale [3 ]
Jacobsen, Helmut [2 ]
Ozmen, Laurence [2 ]
Baumann, Karlheinz [2 ]
机构：
[1] F Hoffmann La Roche Ltd, Discovery Chem, CH-4070 Basel, Switzerland
[2] F Hoffmann La Roche Ltd, CNS Discovery, CH-4070 Basel, Switzerland
[3] F Hoffmann La Roche Ltd, Nonclin Safety, CH-4070 Basel, Switzerland
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 21期
关键词：
Alzheimer's disease; gamma-Secretase modulator; Amyloid-beta peptide; A beta 42 lowering; APPSwe mice model; ALZHEIMERS-DISEASE; BETA; PRESENILIN-1;
D O I：
10.1016/j.bmcl.2011.08.060
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
We herein report the discovery of a new c-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (A beta) peptide production. Overall gamma-secretase is not inhibited but the formation of the aggregating, toxic A beta 42 peptide is shifted to smaller non-aggregating A beta peptides. Compound 15 reduced brain A beta 42 in vivo in APPSwe transgenic mice at 30 mg/kg p.o. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码：6554 / 6558
页数：5
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