BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs).
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described the lead generation effort which resulted, with the support of X-ray crystallography, in the discovery of potent inhibitors based on a hydroxy ethylamine (HEA) transition-state mimetic. These inhibitors were capable of lowering amyloid production in a cell-based assay.
Clarke
Brian
B
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
Faller
Andrew
A
Hawkins
Julie
J
Hussain
Ishrut
I
MacPherson
David
D
Maile
Graham
G
Matico
Rosalie
R
Milner
Peter
P
Mosley
Julie
J
Naylor
Alan
A
O'Brien
Alistair
A
Redshaw
Sally
S
Riddell
David
D
Rowland
Paul
P
Soleil
Virginie
V
Smith
Kathrine J
KJ
Stanway
Steven
S
Stemp
Geoffrey
G
Sweitzer
Sharon
S
Theobald
Pam
P
Vesey
David
D
Walter
Daryl S
DS
Ward
John
J
Wayne
Gareth
G
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; 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*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D016564:Amyloid beta-Protein Precursor; D005021:Ethylamines; D016282:Aspartic Acid Endopeptidases; C041564:ethylamine