Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics.
Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer's disease. We have recently disclosed a series of transition-state mimetic BACE-1 inhibitors showing nanomolar potency in cell-based assays. Amongst them, GSK188909 (compound 2) had favorable pharmacokinetics and was the first orally bioavailable inhibitor reported to demonstrate brain amyloid lowering in an animal model. In this Letter, we describe the reasons that led us to favor a second generation of inhibitors for further in vivo studies.
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Nicolas
N
Charrier
Brian
B
Clarke
Leanne
L
Cutler
Emmanuel
E
Demont
Colin
C
Dingwall
Rachel
R
Dunsdon
Julie
J
Hawkins
Colin
C
Howes
Julia
J
Hubbard
Ishrut
I
Hussain
Graham
G
Maile
Rosalie
R
Matico
Julie
J
Mosley
Alan
A
Naylor
Alistair
A
O'Brien
Sally
S
Redshaw
Paul
P
Rowland
Virginie
V
Soleil
Kathrine J
KJ
Smith
Sharon
S
Sweitzer
Pam
P
Theobald
David
D
Vesey
Daryl S
DS
Walter
Gareth
G
Wayne
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; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D005021:Ethylamines; C518127:GSK188909; D011480:Protease Inhibitors; D013843:Thiazines; D016282:Aspartic Acid Endopeptidases