Clarke Brian, Demont Emmanuel, Dingwall Colin, Dunsdon Rachel, Faller Andrew, Hawkins Julie, Hussain Ishrut, MacPherson David, Maile Graham, Matico Rosalie, Milner Peter, Mosley Julie, Naylor Alan, O'Brien Alistair, Redshaw Sally, Riddell David, Rowland Paul, Soleil Virginie, Smith Kathrine J, Stanway Steven, Stemp Geoffrey, Sweitzer Sharon, Theobald Pam, Vesey David, Walter Daryl S, Ward John, 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. 2008 Feb 1;18(3):1011-6. doi: 10.1016/j.bmcl.2007.12.017. Epub 2007 Dec 15.
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
抑制天冬氨酰蛋白酶BACE-1有可能为阿尔茨海默病提供一种改善病情的疗法。本文描述了先导化合物的研发过程，该过程在X射线晶体学的支持下，基于羟乙胺（HEA）过渡态模拟物发现了强效抑制剂。这些抑制剂能够在细胞试验中降低淀粉样蛋白的产生。
