title: Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics.
abstract: Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
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: Leanne
authors.initials: L
authors.lastname: Cutler
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: Colin
authors.initials: C
authors.lastname: Howes
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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001682:Biological Availability; D004285:Dogs; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D005021:Ethylamines; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases