Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide gamma-secretase inhibitors.
gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.
Pu
Jun
J
Chemical Sciences, Wyeth Research, Princeton, NJ 08543-8000, USA.
Kreft
Anthony F
AF
Aschmies
Suzan H
SH
Atchison
Kevin P
KP
Berkowitz
Joshua
J
Caggiano
Thomas J
TJ
Chlenov
Micheal
M
Diamantidis
George
G
Harrison
Boyd L
BL
Hu
Yun
Y
Huryn
Donna
D
Steven Jacobsen
J
J
Jin
Mei
M
Lipinski
Kerri
K
Lu
Peimin
P
Martone
Robert L
RL
Morris
Koi
K
Sonnenberg-Reines
June
J
Riddell
Dave R
DR
Sabalski
Joan
J
Sun
Shaiu-Ching
SC
Wagner
Erik
E
Wang
Yiqun
Y
Xu
Zheng
Z
Zhou
Hua
H
Resnick
Lynn
L
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D051880:Receptors, Notch / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D006571:Heterocyclic Compounds; D051880:Receptors, Notch; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases