Macrocyclic peptidomimetic β-secretase (BACE-1) inhibitors with activity in vivo

被引：46

作者：

Machauer, Rainer ^{[1
]}

Laumen, Kurt ^{[1
]}

Veenstra, Siem ^{[1
]}

Rondeau, Jean-Michel ^{[1
]}

Tintelnot-Blomley, Marina ^{[1
]}

Betschart, Claudia ^{[1
]}

Jaton, Anne-Lise ^{[1
]}

Desrayaud, Sandrine ^{[1
]}

Staufenbiel, Matthias ^{[1
]}

Rabe, Sabine ^{[1
]}

Paganetti, Paolo ^{[1
]}

Neumann, Ulf ^{[1
]}

机构：

[1] Novartis Pharma AG, Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 05期

关键词：

Alzheimer's disease; BACE-1; inhibition; Macrocycles; Ethanolamine-transition state mimetic; In vivo efficacy in APP51/16 mice; AMYLOID PRECURSOR PROTEIN; STRUCTURE-BASED DESIGN; ASPARTIC PROTEASE; ALZHEIMERS-DISEASE; PURIFICATION;

D O I：

10.1016/j.bmcl.2009.01.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The macrocyclic peptidic BACE-1 inhibitors 2a-c show moderate enzymatic and cellular activity. By exchange of the hydroxyethylene- to ethanolamine-transition state mimetic the peptidic character was reduced, providing the highly potent and selective inhibitor 3. Variation of the P' moiety resulted in the macrocyclic inhibitor 14. Both macrocycles show inhibition of BACE-1 in the brain of APP51/16 transgenic mice, 3 (NB-544) after intravenous and 14 (NB-533) after oral application. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1366 / 1370

页数：5

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