title: Potent benzoazepinone γ-secretase modulators with improved bioavailability.
abstract: The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat.
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: joey_methot@merck.com.
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Chaomin
authors.initials: C
authors.lastname: Li
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Rivkin
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Ahearn
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: William Colby
authors.initials: WC
authors.lastname: Brown
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Kattar
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kelley
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Mampreian
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Schell
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenau
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Ball
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sujal V
authors.initials: SV
authors.lastname: Deshmukh
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Valentina V
authors.initials: VV
authors.lastname: Jeliazkova-Mecheva
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Damaris
authors.initials: D
authors.lastname: Diaz
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Lily Y
authors.initials: LY
authors.lastname: Moy
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Moxham
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Shah
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Hugh
authors.initials: H
authors.lastname: Nuthall
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Armetta
authors.initials: A
authors.lastname: Hill
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Nadya
authors.initials: N
authors.lastname: Smotrov
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
authors.affiliation: Merck Research Laboratories, 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 / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats
chemical_list: D053829:Amyloid Precursor Protein Secretases
keywords: Bioavailability; Pharmacokinetics; γ-Secretase modulator