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.
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
Cutler
Leanne
L
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
Hawkins
Julie
J
Howes
Colin
C
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; 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