gamma-secretase modulator 1 - CAS 1172637-87-4
Catalog number: 1172637-87-4
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
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gamma-secretase modulator 1 is a gamma-secretase modulator, useful for Alzheimer's disease.
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1.Single administration of a novel γ-secretase modulator ameliorates cognitive dysfunction in aged C57BL/6J mice.
Hayama T1, Murakami K1, Watanabe T1, Maeda R1, Kamata M1, Kondo S2. Brain Res. 2016 Feb 15;1633:52-61. doi: 10.1016/j.brainres.2015.12.020. Epub 2015 Dec 17.
Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early onset of Alzheimer׳s disease (AD). These proteins comprise the catalytic domain of γ-secretase, which catalyzes the cleavage of β-amyloid (Aβ) from amyloid precursor protein (APP). In recent reports, PS1 and PS2 were linked to the modulation of intracellular calcium ion (Ca(2+)) dynamics, a key regulator of synaptic function. Ca(2+) dysregulation and synaptic dysfunction are leading hypothesis of cognitive dysfunctions during aging and AD progression. Accordingly, manipulations of presenilins by small molecules may have therapeutic potential for the treatment of cognitive dysfunction. In an accompanying report, we showed that chronic treatment with compound-1, a novel γ-secretase modulator (GSM), reduced Aβ production and ameliorated cognitive dysfunction in Tg2576 APP transgenic mice. Accordingly, in the present study we showed that single oral administration of compound-1 at 1 and 3mg/kg ameliorated cognitive dysfunction in aged non-transgenic mice.
2.Identification of the novel activity-driven interaction between synaptotagmin 1 and presenilin 1 links calcium, synapse, and Kuzuya A1, Zoltowska KM1, Post KL1, Arimon M1, Li X1, Svirsky S1, Maesako M1, Muzikansky A2, Gautam V1, Kovacs D1, Hyman BT1, Berezovska O3. BMC Biol. 2016 Mar 31;14:25. doi: 10.1186/s12915-016-0248-3.
BACKGROUND: Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid β (Aβ) peptide, and neurotoxic Aβ42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aβ production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer's disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins.
3.Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aβ₄₂ production.
Takai T1, Koike T2, Honda E2, Kajita Y2, Nakamura M2, Morimoto S2, Hoashi Y2, Kamata M2, Watanabe T2, Igari T2, Terauchi J2. Bioorg Med Chem. 2015 May 1;23(9):1923-34. doi: 10.1016/j.bmc.2015.03.055. Epub 2015 Mar 28.
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.
4.Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans.
Ling IF1, Golde TE2, Galasko DR1, Koo EH3. Alzheimers Res Ther. 2015 Aug 5;7(1):55. doi: 10.1186/s13195-015-0137-y. eCollection 2015.
INTRODUCTION: Ibuprofen is one of the nonsteroidal anti-inflammatory drugs that have been shown to selectively lower pathogenic amyloid beta-peptide (Aβ)42 without impairing overall γ-secretase activity in vitro. This γ-secretase modulator (GSM) activity has been hypothesized to contribute to the reduction in risk of developing Alzheimer's disease in chronic users of nonsteroidal anti-inflammatory drugs. However, it is unclear whether ibuprofen, within therapeutic dosing range, demonstrates GSM activity in humans. In this study, we evaluated the effects of ibuprofen and a second-generation GSM, GSM-1, on Aβ levels in cerebrospinal fluid and plasma of young nonhuman primates and humans.
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