Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics.
Our first generation of hydroxyethylamine BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001682:Biological Availability; D004285:Dogs; D005021:Ethylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D005021:Ethylamines; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases