title: Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.
abstract: 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.
authors.affiliation: Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charrier
authors.forename: Brian
authors.initials: B
authors.lastname: Clarke
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Demont
authors.forename: Colin
authors.initials: C
authors.lastname: Dingwall
authors.forename: Rachel
authors.initials: R
authors.lastname: Dunsdon
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.forename: Julia
authors.initials: J
authors.lastname: Hubbard
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: Graham
authors.initials: G
authors.lastname: Maile
authors.forename: Rosalie
authors.initials: R
authors.lastname: Matico
authors.forename: Julie
authors.initials: J
authors.lastname: Mosley
authors.forename: Alan
authors.initials: A
authors.lastname: Naylor
authors.forename: Alistair
authors.initials: A
authors.lastname: O'Brien
authors.forename: Sally
authors.initials: S
authors.lastname: Redshaw
authors.forename: Paul
authors.initials: P
authors.lastname: Rowland
authors.forename: Virginie
authors.initials: V
authors.lastname: Soleil
authors.forename: Kathrine J
authors.initials: KJ
authors.lastname: Smith
authors.forename: Sharon
authors.initials: S
authors.lastname: Sweitzer
authors.forename: Pam
authors.initials: P
authors.lastname: Theobald
authors.forename: David
authors.initials: D
authors.lastname: Vesey
authors.forename: Daryl S
authors.initials: DS
authors.lastname: Walter
authors.forename: Gareth
authors.initials: G
authors.lastname: Wayne
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D005021:Ethylamines; C518127:GSK188909; D011480:Protease Inhibitors; D013843:Thiazines; D016282:Aspartic Acid Endopeptidases