BACE-1 inhibitors part 2: identification of hydroxy ethylamines (HEAs) with reduced peptidic character.
This paper describes the discovery of non-peptidic, potent, and selective hydroxy ethylamine (HEA) inhibitors of BACE-1 by replacement of the prime side of a lead di-amide 2. Inhibitors with nanosmolar potency and high selectivity were identified. Depending on the nature of the P(1)(') and P(2)(') substituents, two different binding modes were observed in X-ray co-crystal structures.
Clarke
Brian
B
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
Faller
Andrew
A
Hawkins
Julie
J
Hussain
Ishrut
I
MacPherson
David
D
Maile
Graham
G
Matico
Rosalie
R
Milner
Peter
P
Mosley
Julie
J
Naylor
Alan
A
O'Brien
Alistair
A
Redshaw
Sally
S
Riddell
David
D
Rowland
Paul
P
Soleil
Virginie
V
Smith
Kathrine J
KJ
Stanway
Steven
S
Stemp
Geoffrey
G
Sweitzer
Sharon
S
Theobald
Pam
P
Vesey
David
D
Walter
Daryl S
DS
Ward
John
J
Wayne
Gareth
G
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D016564:Amyloid beta-Protein Precursor; D005021:Ethylamines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C041564:ethylamine