Discovery of sulfonamide-pyrazole gamma-secretase inhibitors.
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
Mattson
Matthew N
MN
Elan Pharmaceuticals, 800 Gateway Blvd., South San Francisco, CA 94080, United States.
Neitzel
Martin L
ML
Quincy
David A
DA
Semko
Christopher M
CM
Garofalo
Albert W
AW
Keim
Pamela S
PS
Konradi
Andrei W
AW
Pleiss
Michael A
MA
Sham
Hing L
HL
Brigham
Elizabeth F
EF
Goldbach
Erich G
EG
Zhang
Hongbin
H
Sauer
John-Michael
JM
Basi
Guriqbal S
GS
D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D011720:Pyrazoles; D013449:Sulfonamides; C031280:pyrazole; D053829:Amyloid Precursor Protein Secretases