title: Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aβ₄₂ production.
abstract: Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ₄₂ production. Lead compound 3, with selective Aβ₄₂-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aβ₄₂ in mice.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takafumi.takai@takeda.com.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Takai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koike
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Honda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kajita
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Sachie
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Hoashi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Igari
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry; D000077489:Piperazine; D010879:Piperazines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010879:Piperazines; C075222:amyloid beta-protein (1-42); D000077489:Piperazine; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Amyloid beta; γ-Secretase modulator