title: Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators.
abstract: Novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives were designed, synthesized, and evaluated as γ-secretase modulators (GSMs). An optimization study of this series resulted in the identification of (R)-11j, which showed a potent Aβ42-lowering effect, high bioavailability and good blood-brain barrier permeability in mice. Oral administration of (R)-11j significantly reduced brain Aβ42 in mice at a dose of 10 mg/kg.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takafumi.takai@takeda.com.
authors: Takafumi
authors: T
authors: Takai
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yasutaka
authors: Y
authors: Hoashi
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Yoshihide
authors: Y
authors: Tomata
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Sachie
authors: S
authors: Morimoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Minoru
authors: M
authors: Nakamura
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Tomomichi
authors: T
authors: Watanabe
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Tomoko
authors: T
authors: Igari
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors: Tatsuki
authors: T
authors: Koike
mesh_terms: D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D011725:Pyridines; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer’s disease; Amyloid beta; γ-Secretase modulators