title: Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.
abstract: The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
authors: Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States. danielle.aubele@elan.com
authors: Danielle L
authors: DL
authors: Aubele
authors: Anh P
authors: AP
authors: Truong
authors: Darren B
authors: DB
authors: Dressen
authors: Gary D
authors: GD
authors: Probst
authors: Simeon
authors: S
authors: Bowers
authors: Matthew N
authors: MN
authors: Mattson
authors: Chris M
authors: CM
authors: Semko
authors: Minghua
authors: M
authors: Sun
authors: Albert W
authors: AW
authors: Garofalo
authors: Andrei W
authors: AW
authors: Konradi
authors: Hing L
authors: HL
authors: Sham
authors: Wes
authors: W
authors: Zmolek
authors: Karina
authors: K
authors: Wong
authors: Erich
authors: E
authors: Goldbach
authors: Kevin P
authors: KP
authors: Quinn
authors: John-Michael
authors: JM
authors: Sauer
authors: Elizabeth F
authors: EF
authors: Brigham
authors: William
authors: W
authors: Wallace
authors: Lan
authors: L
authors: Nguyen
authors: Michael P
authors: MP
authors: Bova
authors: Susanna S
authors: SS
authors: Hemphill
authors: Guriqbal
authors: G
authors: Basi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008815:Mice, Inbred Strains; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D013449:Sulfonamides; D053829:Amyloid Precursor Protein Secretases