title: BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character.
abstract: This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
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: 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: Andrew
authors.initials: A
authors.lastname: Faller
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: David
authors.initials: D
authors.lastname: MacPherson
authors.forename: Graham
authors.initials: G
authors.lastname: Maile
authors.forename: Rosalie
authors.initials: R
authors.lastname: Matico
authors.forename: Peter
authors.initials: P
authors.lastname: Milner
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: David
authors.initials: D
authors.lastname: Riddell
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: Steven
authors.initials: S
authors.lastname: Stanway
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Stemp
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: John
authors.initials: J
authors.lastname: Ward
authors.forename: Gareth
authors.initials: G
authors.lastname: Wayne
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D016564:Amyloid beta-Protein Precursor; D005021:Ethylamines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C041564:ethylamine