Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors.
Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.
Ye
Xiaocong M
XM
Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States. michael.ye@elan.com
Konradi
Andrei W
AW
Smith
Jenifer
J
Xu
Ying-Zi
YZ
Dressen
Darren
D
Garofalo
Albert W
AW
Marugg
Jennifer
J
Sham
Hing L
HL
Truong
Anh P
AP
Jagodzinski
Jacek
J
Pleiss
Michael
M
Zhang
Hongbin
H
Goldbach
Erich
E
Sauer
John-Michael
JM
Brigham
Elizabeth
E
Bova
Michael
M
Basi
Guriqbal S
GS
D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
D010880:Piperidines; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases