Rapid P1 SAR of brain penetrant tertiary carbinamine derived BACE inhibitors

被引：17

作者：

Zhu, Hong ^{[1
]}

Young, Mary B. ^{[1
]}

Nantermet, Philippe G. ^{[1
]}

Graham, Samuel L. ^{[1
]}

Colussi, Dennis ^{[2
]}

Lai, Ming-Tain ^{[2
]}

Pietrak, Beth ^{[2
]}

Price, Eric A. ^{[2
]}

Sankaranarayanan, Sethu ^{[2
]}

Shi, Xiao-ping ^{[2
]}

Tugusheva, Katherine ^{[2
]}

Holahan, Marie A. ^{[3
]}

Michener, Maria S. ^{[3
]}

Cook, Jacquelynn J. ^{[3
]}

Simon, Adam ^{[2
]}

Hazuda, Daria J. ^{[2
]}

Vacca, Joseph P. ^{[1
]}

Rajapakse, Hemaka A. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Alzheimers Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Imaging Res, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 05期

关键词：

BACE; AD; Tertiary carbinamine; CEREBROSPINAL-FLUID; ALZHEIMERS-DISEASE; BETA-SITE; DISCOVERY; PROTEASE; PROGRESS;

D O I：

10.1016/j.bmcl.2010.01.005

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF A beta 40 was observed. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：1779 / 1782

页数：4

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