title: Discovery of novel triazolobenzazepinones as γ-secretase modulators with central Aβ42 lowering in rodents and rhesus monkeys.
abstract: Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aβ42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aβ42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aβ42 levels.
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: Christian_fischer@merck.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Zultanski
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hayashi
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Hughes
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Moxham
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Bays
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Nadya
authors.initials: N
authors.lastname: Smotrov
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Armetta D
authors.initials: AD
authors.lastname: Hill
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Bo-Sheng
authors.initials: BS
authors.lastname: Pan
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Flobert
authors.initials: F
authors.lastname: Tanga
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Candia
authors.initials: C
authors.lastname: Kenific
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Walker
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bouthillette
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: George N
authors.initials: GN
authors.lastname: Nikov
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sujal V
authors.initials: SV
authors.lastname: Deshmukh
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Valentina V
authors.initials: VV
authors.lastname: Jeliazkova-Mecheva
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Damaris
authors.initials: D
authors.lastname: Diaz
authors.affiliation: Merck Research Laboratories West Point, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.affiliation: Merck Research Laboratories West Point, 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Merck Research Laboratories Boston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shearman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D055808:Drug Discovery; D008253:Macaca mulatta; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s; CSF Aβ lowering; GSM; Rhesus PK/PD; γ-Secretase