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Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease
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O'Hare, Eugene, Scopes, David I. C., Kim, Eun-Mee, Palmer, P. (Philip), Spanswick, David, McMahon, Bridgeen, Amijee, Hozefa, Nerou, Edmund, Treherne, J. Mark and Jeggo, Ross (2014) Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease. The International Journal of Neuropsychopharmacology, Volume 17 (Number 1). pp. 117-126. doi:10.1017/S1461145713000886 ISSN 1461-1457.
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Official URL: http://dx.doi.org/10.1017/S1461145713000886
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 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.
Item Type: | Journal Article | ||||
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Subjects: | R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry R Medicine > RM Therapeutics. Pharmacology |
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Alzheimer's disease -- Treatment -- Research, Amyloid beta-protein | ||||
Journal or Publication Title: | The International Journal of Neuropsychopharmacology | ||||
Publisher: | Cambridge University Press | ||||
ISSN: | 1461-1457 | ||||
Official Date: | 2014 | ||||
Dates: |
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Volume: | Volume 17 | ||||
Number: | Number 1 | ||||
Page Range: | pp. 117-126 | ||||
DOI: | 10.1017/S1461145713000886 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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