Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics
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- 作者：Nicolas Charrier ; Brian Clarke ; Leanne Cutler ; Emmanuel Demont ; Colin Dingwall ; Rachel Dunsdon ; Julie Hawkins ; Colin Howes ; Julia Hubbard ; Ishrut Hussain ; Graham Maile ; Rosalie Matico ; Julie Mosley ; A
- 关键词：Alzheimer ; BACE-1 ; Aspartic protease ; Hydroxyethylamine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2009
- 出版时间：1 July 2009
- 年：2009
- 卷：19
- 期：13
- 页码：3664-3668
- 全文大小：356 K
文摘
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.