Design, synthesis, and structure-activity relationship of novel orally efficacious pyrazole/sulfonamide based dihydroquinoline gamma-secretase inhibitors.
In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.
Truong
Anh P
AP
Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA.
Aubele
Danielle L
DL
Probst
Gary D
GD
Neitzel
Martin L
ML
Semko
Chris M
CM
Bowers
Simeon
S
Dressen
Darren
D
Hom
Roy K
RK
Konradi
Andrei W
AW
Sham
Hing L
HL
Garofalo
Albert W
AW
Keim
Pamela S
PS
Wu
Jing
J
Dappen
Michael S
MS
Wong
Karina
K
Goldbach
Erich
E
Quinn
Kevin P
KP
Sauer
John-Michael
JM
Brigham
Elizabeth F
EF
Wallace
William
W
Nguyen
Lan
L
Hemphill
Susanna S
SS
Bova
Michael P
MP
Bard
Frédérique
F
Yednock
Ted A
TA
Basi
Guriqbal
G
D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
D011480:Protease Inhibitors; D011720:Pyrazoles; D011804:Quinolines; D013449:Sulfonamides; C031280:pyrazole; D053829:Amyloid Precursor Protein Secretases