title: Design and synthesis of bicyclic heterocycles as potent γ-secretase modulators.
abstract: The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
authors.affiliation: Neuroscience, Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium. doehlric@its.jnj.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Oehlrich
authors.forename: Frederik J R
authors.initials: FJ
authors.lastname: Rombouts
authors.forename: Didier
authors.initials: D
authors.lastname: Berthelot
authors.forename: François P
authors.initials: FP
authors.lastname: Bischoff
authors.forename: Michel A J
authors.initials: MA
authors.lastname: De Cleyn
authors.forename: Libuse
authors.initials: L
authors.lastname: Jaroskova
authors.forename: Gregor
authors.initials: G
authors.lastname: Macdonald
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: Michel
authors.initials: M
authors.lastname: Surkyn
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Trabanco
authors.forename: Gary
authors.initials: G
authors.lastname: Tresadern
authors.forename: Sven
authors.initials: S
authors.lastname: Van Brandt
authors.forename: Adriana I
authors.initials: AI
authors.lastname: Velter
authors.forename: Tongfei
authors.initials: T
authors.lastname: Wu
authors.forename: Harrie J M
authors.initials: HJ
authors.lastname: Gijsen
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D010880:Piperidines; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; γ-Secretase modulators