BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296.
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.
Clarke
Brian
B
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Harlow, Essex, UK.
Cutler
Leanne
L
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
Hawkins
Julie
J
Howes
Colin
C
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
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D005021:Ethylamines; D011480:Protease Inhibitors; D001120:Arginine; D053829:Amyloid Precursor Protein Secretases