title: Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability.
abstract: BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
authors.affiliation: Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, UK.
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: Philip
authors.initials: P
authors.lastname: East
authors.forename: Julie
authors.initials: J
authors.lastname: Hawkins
authors.forename: Colin
authors.initials: C
authors.lastname: Howes
authors.forename: Ishrut
authors.initials: I
authors.lastname: Hussain
authors.forename: Phil
authors.initials: P
authors.lastname: Jeffrey
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; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D005021:Ethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D005021:Ethylamines; C570234:N-(1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl)-7-ethyl-1-methyl-3,4-dihydro-1H-(1,2,5)thiadiazepino(3,4,5-hi)indole-9-carboxamide 2,2-dioxide; D053829:Amyloid Precursor Protein Secretases