BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296

Brian Clarke; Leanne Cutler; Emmanuel Demont; Colin Dingwall; Rachel Dunsdon; Julie Hawkins; Colin Howes; Ishrut Hussain; Graham Maile; Rosalie Matico; Julie Mosley; Alan Naylor; Alistair O'Brien; Sally Redshaw; Paul Rowland; Virginie Soleil; Kathrine J Smith; Sharon Sweitzer; Pam Theobald; David Vesey; Daryl S Walter; Gareth Wayne

doi:10.1016/j.bmcl.2010.05.111

BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296

Bioorg Med Chem Lett. 2010 Aug 1;20(15):4639-44. doi: 10.1016/j.bmcl.2010.05.111. Epub 2010 Jun 8.

Affiliation

¹ Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Harlow, Essex, UK.

PMID: 20579874
DOI: 10.1016/j.bmcl.2010.05.111

Abstract

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.

MeSH terms

Alzheimer Disease / drug therapy
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Amyloid Precursor Protein Secretases / metabolism
Animals
Arginine / chemistry*
Binding Sites
Computer Simulation
Crystallography, X-Ray
Ethylamines / chemical synthesis
Ethylamines / chemistry*
Ethylamines / therapeutic use
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / therapeutic use
Rats
Structure-Activity Relationship

Substances

Ethylamines
Protease Inhibitors
Arginine
Amyloid Precursor Protein Secretases