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

Prefibrillar assembly of amyloid- (A) 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 A synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric A(1-42) was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block A(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 A oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of A oligomers in normal rats. SEN1576 bound to monomeric A(1-42), protected neuronal cells exposed to A(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.