Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors.
Alzheimer's disease (AD) is a debilitating disease widely thought to be associated with the accumulation of beta amyloid (Abeta) in the brain. Inhibition of gamma-secretase, one of the enzymes responsible for Abeta production, may be a useful strategy for the treatment of AD. Described below is a series of gamma-secretase inhibitors designed from a scaffold identified by a ROCS [J. Comput. Chem.1996, 17, 1653] search of the corporate database.
Gundersen
Eric
E
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. gundere@wyeth.com
Fan
Kristi
K
Haas
Kimberly
K
Huryn
Donna
D
Steven Jacobsen
J
J
Kreft
Anthony
A
Martone
Robert
R
Mayer
Scott
S
Sonnenberg-Reines
June
J
Sun
Shaiu-Ching
SC
Zhou
Hua
H
D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010880:Piperidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases