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)


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 Aβ 1-42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aβ 1-42-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 Aβ 1-42, protected neuronal cells exposed to Aβ 1-42, 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
JournalInternational Journal of Neuropsychopharmacology
Issue number1
Publication statusPublished - Jan 2014
Externally publishedYes


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

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