title: Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA. gundere@wyeth.com
authors.forename: Eric
authors.initials: E
authors.lastname: Gundersen
authors.forename: Kristi
authors.initials: K
authors.lastname: Fan
authors.forename: Kimberly
authors.initials: K
authors.lastname: Haas
authors.forename: Donna
authors.initials: D
authors.lastname: Huryn
authors.forename: J
authors.initials: J
authors.lastname: Steven Jacobsen
authors.forename: Anthony
authors.initials: A
authors.lastname: Kreft
authors.forename: Robert
authors.initials: R
authors.lastname: Martone
authors.forename: Scott
authors.initials: S
authors.lastname: Mayer
authors.forename: June
authors.initials: J
authors.lastname: Sonnenberg-Reines
authors.forename: Shaiu-Ching
authors.initials: SC
authors.lastname: Sun
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides; D010880:Piperidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases