National Center for
2WF3: Human Bace-1 In Complex With 6-(ethylamino)-n-((1s,2r)-2-hydroxy-3- (((3-(methyloxy)phenyl)methyl)amino)-1-(phenylmethyl)propyl)-1- Methyl-1, 3,4,5-tetrahydro-2,1-benzothiazepine-8-carboxamide 2,2- Dioxide
Bioorg. Med. Chem. Lett. (2009) 19 p.3669-3673
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.