Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent
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- 作者：Nicolas Charrier ; Brian Clarke ; Emmanuel Demont ; Colin Dingwall ; Rachel Dunsdon ; Julie Hawkins ; Julia Hubbard ; Ishrut Hussain ; Graham Maile ; Rosalie Matico ; Julie Mosley ; Alan Naylor ; Alistair Oȁ
- 关键词：Alzheimer ; BACE-1 ; Hydroxyethylamine ; Aspartic protease
- 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：3669-3673
- 全文大小：353 K
文摘
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer’s disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.