Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease

Eugene O'Hare, David I.C. Scopes, Eun-Mee Kim, Philip Palmer, David Spanswick, Bridgeen McMahon, Hozefa Amijee, Edmund Nerou, J. Mark Treherne, Ross Jeggo

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8 Citations (Scopus)

Abstract

Prefibrillar assembly of amyloid-β (Aβ) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aβ synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aβ1–42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aβ1–42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aβ oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aβ oligomers in normal rats. SEN1576 bound to monomeric Aβ1–42, protected neuronal cells exposed to Aβ1–42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.
Original languageEnglish
Pages (from-to)117-126
Number of pages10
JournalThe International Journal of Neuropsychopharmacology
Volume17
Issue number1
Early online date8 Oct 2013
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Alternating-lever cyclic-ratio schedule
  • amyloid-β
  • Alzheimer's disease
  • long-term potentiation
  • oligomeric Aβ

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    O'Hare, E., Scopes, D. I. C., Kim, E-M., Palmer, P., Spanswick, D., McMahon, B., Amijee, H., Nerou, E., Treherne, J. M., & Jeggo, R. (2014). Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease. The International Journal of Neuropsychopharmacology, 17(1), 117-126. https://doi.org/10.1017/S1461145713000886