Charrier Nicolas, Clarke Brian, Demont Emmanuel, Dingwall Colin, Dunsdon Rachel, Hawkins Julie, Hubbard Julia, Hussain Ishrut, Maile Graham, Matico Rosalie, Mosley Julie, Naylor Alan, O'Brien Alistair, Redshaw Sally, Rowland Paul, Soleil Virginie, Smith Kathrine J, Sweitzer Sharon, Theobald Pam, Vesey David, Walter Daryl S, Wayne Gareth
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. doi: 10.1016/j.bmcl.2009.03.150. Epub 2009 Apr 5.
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.
我们第一代羟乙胺过渡态模拟物β-分泌酶1（BACE-1）抑制剂，通过在动物模型中证明淀粉样蛋白水平降低，使我们能够验证BACE-1是阿尔茨海默病的关键靶点，尽管所需剂量相当高。从该系列中找到一种在较低口服剂量下具有活性的分子被证明是困难的，这表明需要找到一系列具有改善药代动力学的新型抑制剂。本信函描述了此类抑制剂的发现。
