BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells.
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
Beswick
Paul
P
Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
Charrier
Nicolas
N
Clarke
Brian
B
Demont
Emmanuel
E
Dingwall
Colin
C
Dunsdon
Rachel
R
Faller
Andrew
A
Gleave
Robert
R
Hawkins
Julie
J
Hussain
Ishrut
I
Johnson
Christopher N
CN
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
Skidmore
John
J
Soleil
Virginie
V
Smith
Kathrine J
KJ
Stanway
Steven
S
Stemp
Geoffrey
G
Stuart
Alistair
A
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*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors; D000818:Animals; D001216:Asparagine / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005461:Fluorine / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D036103:Nanotechnology; D013329:Structure-Activity Relationship
D016564:Amyloid beta-Protein Precursor; D005021:Ethylamines; D005461:Fluorine; D001216:Asparagine; D016282:Aspartic Acid Endopeptidases; C041564:ethylamine