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

Eugene O'Hare, D.I.C. Scopes, Eun-Mee Kim, Philip Palmer, D. Spanswick, Bridgeen McMahon, H. Amijee, E. Nerou, J.M. Treherne, R. Jeggo

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Prefibrillar assembly of amyloid-ß (Aß) 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 Aß synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aß 1–42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aß 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 Aß oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aß oligomers in normal rats. SEN1576 bound to monomeric Aß 1–42, protected neuronal cells exposed to Aß 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
Volume17
Issue number1
Early online date08 Oct 2013
DOIs
Publication statusPublished - Jan 2014

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Psychiatry and Mental health

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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. International Journal of Neuropsychopharmacology, 17(1), 117-126. https://doi.org/10.1017/S1461145713000886