Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1).
We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.
Stachel
Shawn J
SJ
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. shawn_stachel@merck.com
Coburn
Craig A
CA
Steele
Thomas G
TG
Jones
Kristen G
KG
Loutzenhiser
Elizabeth F
EF
Gregro
Alison R
AR
Rajapakse
Hemaka A
HA
Lai
Ming-Tain
MT
Crouthamel
Ming-Chih
MC
Xu
Min
M
Tugusheva
Katherine
K
Lineberger
Janet E
JE
Pietrak
Beth L
BL
Espeseth
Amy S
AS
Shi
Xiao-Ping
XP
Chen-Dodson
Elizabeth
E
Holloway
M Katharine
MK
Munshi
Sanjeev
S
Simon
Adam J
AJ
Kuo
Lawrence
L
Vacca
Joseph P
JP
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015195:Drug Design; D005021:Ethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D005021:Ethylamines; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases