Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.
Mayer
Scott C
SC
Chemical and Screening Sciences, and Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, New Jersey 08543, USA. mayers@wyeth.com
Kreft
Anthony F
AF
Harrison
Boyd
B
Abou-Gharbia
Magid
M
Antane
Madelene
M
Aschmies
Suzan
S
Atchison
Kevin
K
Chlenov
Michael
M
Cole
Derek C
DC
Comery
Thomas
T
Diamantidis
George
G
Ellingboe
John
J
Fan
Kristi
K
Galante
Rocco
R
Gonzales
Cathleen
C
Ho
Douglas M
DM
Hoke
Molly E
ME
Hu
Yun
Y
Huryn
Donna
D
Jain
Uday
U
Jin
Mei
M
Kremer
Kenneth
K
Kubrak
Dennis
D
Lin
Melissa
M
Lu
Peimin
P
Magolda
Ron
R
Martone
Robert
R
Moore
William
W
Oganesian
Aram
A
Pangalos
Menelas N
MN
Porte
Alex
A
Reinhart
Peter
P
Resnick
Lynn
L
Riddell
David R
DR
Sonnenberg-Reines
June
J
Stock
Joseph R
JR
Sun
Shaiu-Ching
SC
Wagner
Erik
E
Wang
Ting
T
Woller
Kevin
K
Xu
Zheng
Z
Zaleska
Margaret M
MM
Zeldis
Joseph
J
Zhang
Minsheng
M
Zhou
Hua
H
Jacobsen
J Steven
JS
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008968:Molecular Conformation; D051881:Receptor, Notch1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D051881:Receptor, Notch1; D013449:Sulfonamides; D013876:Thiophenes; C539549:begacestat; D053829:Amyloid Precursor Protein Secretases