Acylguanidines as small-molecule beta-secretase inhibitors.
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
Cole
Derek C
DC
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. coledc@wyeth.com
Manas
Eric S
ES
Stock
Joseph R
JR
Condon
Jeffrey S
JS
Jennings
Lee D
LD
Aulabaugh
Ann
A
Chopra
Rajiv
R
Cowling
Rebecca
R
Ellingboe
John W
JW
Fan
Kristi Y
KY
Harrison
Boyd L
BL
Hu
Yun
Y
Jacobsen
Steve
S
Jin
Guixan
G
Lin
Laura
L
Lovering
Frank E
FE
Malamas
Michael S
MS
Stahl
Mark L
ML
Strand
James
J
Sukhdeo
Mohani N
MN
Svenson
Kristine
K
Turner
M James
MJ
Wagner
Erik
E
Wu
Junjun
J
Zhou
Ping
P
Bard
Jonathan
J
D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D006146:Guanidines; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases