Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability.
BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.
Charrier
Nicolas
N
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Park, Harlow, Essex, UK.
Clarke
Brian
B
Cutler
Leanne
L
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
East
Philip
P
Hawkins
Julie
J
Howes
Colin
C
Hussain
Ishrut
I
Jeffrey
Phil
P
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; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D005021:Ethylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship
D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D005021:Ethylamines; C570234:N-(1-benzyl-3-(cyclopropylamino)-2-hydroxypropyl)-7-ethyl-1-methyl-3,4-dihydro-1H-(1,2,5)thiadiazepino(3,4,5-hi)indole-9-carboxamide 2,2-dioxide; D053829:Amyloid Precursor Protein Secretases