Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics

被引：46

作者：

Charrier, Nicolas ^{[1
]}

Clarke, Brian ^{[1
]}

Cutler, Leanne ^{[1
]}

Demont, Emmanuel ^{[1
]}

Dingwall, Colin ^{[1
]}

Dunsdon, Rachel ^{[1
]}

Hawkins, Julie ^{[1
]}

Howes, Colin ^{[1
]}

Hubbard, Julia ^{[1
]}

Hussain, Ishrut ^{[1
]}

Maile, Graham ^{[1
]}

Matico, Rosalie ^{[1
]}

Mosley, Julie ^{[1
]}

Naylor, Alan ^{[1
]}

O'Brien, Alistair ^{[1
]}

Redshaw, Sally ^{[1
]}

Rowland, Paul ^{[1
]}

Soleil, Virginie ^{[1
]}

Smith, Kathrine J. ^{[1
]}

Sweitzer, Sharon ^{[1
]}

Theobald, Pam ^{[1
]}

Vesey, David ^{[1
]}

Walter, Daryl S. ^{[1
]}

Wayne, Gareth ^{[1
]}

机构：

[1] GlaxoSmithKline R&D, Neurol & Gastrointestinal Ctr Excellence Drug Dis, Harlow CM19 5AW, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 13期

关键词：

Alzheimer; BACE-1; Apartic protease; Hydroxyethylamine; DISCOVERY; DRUGS;

D O I：

10.1016/j.bmcl.2009.03.149

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：

Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3674 / 3678

页数：5

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