Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: Structure based design and in vivo reduction of amyloid β-peptides

被引：21

作者：

Rueeger, Heinrich ^{[1
]}

Lueoend, Rainer ^{[1
]}

Machauer, Rainer ^{[1
]}

Veenstra, Siem Jacob ^{[1
]}

Jacobson, Laura Helen ^{[2
]}

Staufenbiel, Matthias ^{[2
]}

Desrayaud, Sandrine ^{[3
]}

Rondeau, Jean-Michel ^{[3
]}

Moebitz, Henrik ^{[1
]}

Neumann, Ulf ^{[2
]}

机构：

[1] Novartis Pharma AG, Inst BioMed Res, Dept Global Discovery Chem, CH-4057 Basel, Switzerland

[2] Novartis Pharma AG, Inst BioMed Res, Dept Neurosci, CH-4057 Basel, Switzerland

[3] Novartis Pharma AG, Inst BioMed Res, CH-4057 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 19期

关键词：

BACE-1; Inhibitor; Alzheimer's disease; Structure based design; Cyclic sulfoxide hydroxyethylamine inhibitors; In vivo reduction of amyloid b-peptides; PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; ASYMMETRIC OXIDATION; SECRETASE ACTIVITY; HYDROGEN-PEROXIDE; NERVOUS-SYSTEM; MICE; PHARMACOKINETICS; SULFIDES; BRAIN;

D O I：

10.1016/j.bmcl.2013.07.071

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Ab following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：5300 / 5306

页数：7

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