title: Pharmacological properties of a novel and potent γ-secretase modulator as a therapeutic option for the treatment of Alzheimer's disease.
abstract: Previous studies of γ-secretase inhibitors (GSIs) and Notch-sparing GSIs have shown reduced amyloid-β (Aβ) peptide levels but increased Notch-related and -unrelated adverse effects. In this study, we examined the effects of compound-1 on Aβ processing and cognitive function and assessed Notch-related and -unrelated adverse effects. Compound-1 reduced Aβ40 and Aβ42 levels but inversely increased Aβ37 in Neuro2a cells, leading to no net changes in total Aβ levels, indicating that compound-1 is a γ-secretase modulator (GSM). In time-course experiments, compound-1 reduced Aβ40 and Aβ42 levels in tris-soluble fractions, with peak reduction at approximately 3h after oral administration in C57BL mice. Moreover, at >1mg/kg, compound-1 dose dependently reduced Aβ40 and Aβ42 levels in Tg2576 mice. Chronic treatment with compound-1 in Tg2576 mice for 4 months significantly reduced both soluble and insoluble Aβ42 levels and ameliorated cognitive impairments, even after drug withdrawal for 10 days following oral administration for 2 months. In contrast with compound-1, at 100-fold higher doses (100mg/kg), the GSI LY450139 decreased HES1 mRNA expression in thymus tissues and increased the intensity of periodic acid-Schiff (PAS)-positive areas in the intestine. Moreover, the Notch-sparing GSI BMS708163 led to amyloid precursor protein (APP)-β-C-terminal fragment accumulation in mouse primary neurons. BMS708163 significantly hampered cognitive function in normal mice 1 month after administration, whereas compound-1 significantly improved cognitive function. Taken together, the present novel and orally active GSM is a promising molecule for the treatment of pathologies associated with Aβ42 and Aβ40.
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan.
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Koike
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Igari
authors.affiliation: CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa 251-8555, Japan. Electronic address: shinichi.kondou@takeda.com.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kondo
mesh_terms: D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C000613083:2-(3-(3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl) -8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro(1,2,4)triazolo(4,3-a)pyridin-8-yl)propan-2-ol; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D011725:Pyridines; D014230:Triazoles; D053829:Amyloid Precursor Protein Secretases
keywords: Aβ; Compound-1; γ-Secretase inhibitor; γ-Secretase modulator