Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.
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.
Charrier
Nicolas
N
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Clarke
Brian
B
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
Hawkins
Julie
J
Hubbard
Julia
J
Hussain
Ishrut
I
Maile
Graham
G
Matico
Rosalie
R
Mosley
Julie
J
Naylor
Alan
A
O'Brien
Alistair
A
Redshaw
Sally
S
Rowland
Paul
P
Soleil
Virginie
V
Smith
Kathrine J
KJ
Sweitzer
Sharon
S
Theobald
Pam
P
Vesey
David
D
Walter
Daryl S
DS
Wayne
Gareth
G
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
D016229:Amyloid beta-Peptides; D005021:Ethylamines; C518127:GSK188909; D011480:Protease Inhibitors; D013843:Thiazines; D016282:Aspartic Acid Endopeptidases