Discovery of a novel series of Notch-sparing gamma-secretase inhibitors.
Using a cell-based assay, we have identified a new series of Notch-sparing gamma-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved gamma-secretase inhibitory potency and Notch-sparing selectivity.
Kreft
Anthony
A
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. krefta@wyeth.com
Harrison
Boyd
B
Aschmies
Suzan
S
Atchison
Kevin
K
Casebier
David
D
Cole
Derek C
DC
Diamantidis
George
G
Ellingboe
John
J
Hauze
Diane
D
Hu
Yun
Y
Huryn
Donna
D
Jin
Mei
M
Kubrak
Dennis
D
Lu
Peimin
P
Lundquist
Joseph
J
Mann
Charles
C
Martone
Robert
R
Moore
William
W
Oganesian
Aram
A
Porte
Alex
A
Riddell
Dave R
DR
Sonnenberg-Reines
June
J
Stock
Joseph R
JR
Sun
Shaiu-Ching
SC
Wagner
Erik
E
Woller
Kevin
K
Xu
Zheng
Z
Zhou
Hua
H
Steven Jacobsen
J
J
D000544:Alzheimer Disease / Q000188:drug therapy; D000682:Amyloid / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000682:Amyloid; D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D002244:Carbon; D053829:Amyloid Precursor Protein Secretases