β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer's Disease

被引：116

作者：

Hilpert, Hans ^{[1
]}

Guba, Wolfgang ^{[1
]}

Woltering, Thomas J. ^{[1
]}

Wostl, Wolfgang ^{[1
]}

Pinard, Emmanuel ^{[1
]}

Mauser, Harald ^{[1
]}

Mayweg, Alexander V. ^{[1
]}

Rogers-Evans, Mark ^{[1
]}

Humm, Roland ^{[1
]}

Krummenacher, Daniela ^{[1
]}

Muser, Thorsten ^{[1
]}

Schnider, Christian ^{[1
]}

Jacobsen, Helmut ^{[2
]}

Ozmen, Laurence ^{[2
]}

Bergadano, Alessandra ^{[2
]}

Banner, David W. ^{[3
]}

Hochstrasser, Remo ^{[3
]}

Kuglstatter, Andreas ^{[3
]}

David-Pierson, Pascale ^{[4
]}

Fischer, Holger ^{[4
]}

Polara, Alessandra ^{[5
]}

Narquizian, Robert ^{[5
]}

机构：

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

[2] F Hoffmann La Roche Ltd, PRED, DTA Neurosci, CH-4070 Basel, Switzerland

[3] F Hoffmann La Roche Ltd, PRED, Discovery Technol, CH-4070 Basel, Switzerland

[4] F Hoffmann La Roche Ltd, PRED, Drug Metab & Pharmacokinet, CH-4070 Basel, Switzerland

[5] F Hoffmann La Roche Ltd, PRED, Roche Partnering, CH-4070 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 10期

关键词：

AMYLOID PRECURSOR PROTEIN; ASYMMETRIC-SYNTHESIS; DISCOVERY; REDUCTION; PATHOLOGY; SITE; MYELINATION; CLEAVAGE; COMPLEX; DESIGN;

D O I：

10.1021/jm400225m

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pK(a) and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF A beta 40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of A beta 40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

引用

页码：3980 / 3995

页数：16

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