title: Amino-caprolactam γ-secretase inhibitors showing potential for the treatment of Alzheimer's disease.
abstract: Herein we describe the structure-activity relationship (SAR) of amino-caprolactam analogs derived from amino-caprolactam benzene sulfonamide 1, highlighting affects on the potency of γ-secretase inhibition, selectivity for the inhibition of APP versus Notch processing by γ-secretase and selected pharmakokinetic properties. Amino-caprolactams that are efficacious in reducing the cortical Aβ(x-40) levels in FVB mice via a single 100 mpk IP dose are highlighted.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals, South San Francisco, CA 94080, United States.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Neitzel
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Aubele
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Marugg
authors.forename: Jacek J
authors.initials: JJ
authors.lastname: Jagodzinski
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pleiss
authors.forename: Balazs
authors.initials: B
authors.lastname: Szoke
authors.forename: Wes
authors.initials: W
authors.lastname: Zmolek
authors.forename: Erich
authors.initials: E
authors.lastname: Goldbach
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Brigham
authors.forename: William
authors.initials: W
authors.lastname: Wallace
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Susanna
authors.initials: S
authors.lastname: Hemphill
authors.forename: Guriqbal
authors.initials: G
authors.lastname: Basi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002209:Caprolactam / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D007263:Infusions, Parenteral; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D002209:Caprolactam; D053829:Amyloid Precursor Protein Secretases