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.
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. krefta@wyeth.com
Anthony
A
Kreft
Boyd
B
Harrison
Suzan
S
Aschmies
Kevin
K
Atchison
David
D
Casebier
Derek C
DC
Cole
George
G
Diamantidis
John
J
Ellingboe
Diane
D
Hauze
Yun
Y
Hu
Donna
D
Huryn
Mei
M
Jin
Dennis
D
Kubrak
Peimin
P
Lu
Joseph
J
Lundquist
Charles
C
Mann
Robert
R
Martone
William
W
Moore
Aram
A
Oganesian
Alex
A
Porte
Dave R
DR
Riddell
June
J
Sonnenberg-Reines
Joseph R
JR
Stock
Shaiu-Ching
SC
Sun
Erik
E
Wagner
Kevin
K
Woller
Zheng
Z
Xu
Hua
H
Zhou
J
J
Steven Jacobsen
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