Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.
Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.
Sealy
Jennifer M
JM
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
Truong
Anh P
AP
Tso
Luke
L
Probst
Gary D
GD
Aquino
Jose
J
Hom
Roy K
RK
Jagodzinska
Barbara M
BM
Dressen
Darren
D
Wone
David W G
DW
Brogley
Louis
L
John
Varghese
V
Tung
Jay S
JS
Pleiss
Michael A
MA
Tucker
John A
JA
Konradi
Andrei W
AW
Dappen
Michael S
MS
Toth
Gergely
G
Pan
Hu
H
Ruslim
Lany
L
Miller
Jim
J
Bova
Michael P
MP
Sinha
Sukanto
S
Quinn
Kevin P
KP
Sauer
John-Michael
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human