(S)-N-(5-Chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol a Notch-1-sparing gamma-secretase inhibitor.
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
Cole
Derek C
DC
Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. coledc@wyeth.com
Stock
Joseph R
JR
Kreft
Anthony F
AF
Antane
Madelene
M
Aschmies
Suzan H
SH
Atchison
Kevin P
KP
Casebier
David S
DS
Comery
Thomas A
TA
Diamantidis
George
G
Ellingboe
John W
JW
Harrison
Boyd L
BL
Hu
Yun
Y
Jin
Mei
M
Kubrak
Dennis M
DM
Lu
Peimin
P
Mann
Charles W
CW
Martone
Robert L
RL
Moore
William J
WJ
Oganesian
Aram
A
Riddell
David R
DR
Sonnenberg-Reines
June
J
Sun
Shaiu-Ching
SC
Wagner
Erik
E
Wang
Zheng
Z
Woller
Kevin R
KR
Xu
Zheng
Z
Zhou
Hua
H
Jacobsen
J Steven
JS
D000438:Alcohols; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D015195:Drug Design; D006801:Humans; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000737:chemistry; D008956:Models, Chemical; D011412:Propanolamines / Q000737:chemistry; D051881:Receptor, Notch1 / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry
C539992:(S)-4-chlorophenylsulfonyl isoleucinol; D000438:Alcohols; D016564:Amyloid beta-Protein Precursor; D011412:Propanolamines; D051881:Receptor, Notch1; D013449:Sulfonamides; D007532:Isoleucine; C014060:isoleucinol; C034448:2-aminopropanol; D053829:Amyloid Precursor Protein Secretases