Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics

被引：45

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; Aspartic protease; Hydroxyethylamine; AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE; ALZHEIMERS-DISEASE; IN-VIVO; IDENTIFICATION; PURIFICATION; CLEAVAGE; POTENCY;

D O I：

10.1016/j.bmcl.2009.03.165

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：

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3664 / 3668

页数：5

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