RS-0406 Arrests Amyloid-β Oligomer-Induced Behavioural Deterioration In Vivo

Development and validation of a yeast high-throughput screen for inhibitors of Aβ42 oligomerization

“…SEN304 has been reported to inhibit secretion of toxic sodium dodecyl sulfate (SDS)-stable oligomers in 7PA2 cells (Kokkoni et al, 2006). Other compounds that are known to inhibit Aβ 42 from forming toxic oligomers and that also have a therapeutic effect in AD animal models are: curcumin (Yang et al, 2005), RS-0406 (hydroxyanaline) (Nakagami et al, 2002; O’Hare et al, 2010; Walsh et al, 2005), SEN1269 (hydroxyanaline derivative; Senexis), scyllo-inositol (AZD-103) (McLaurin et al, 2000; McLaurin et al, 2006; Townsend et al, 2006), PBT1 (Clioquinol, 8-hydroxyquinolin) (Hsiao et al, 1996) and PBT2 (a copper/zinc ionophore, 8-hydroxyquinolin) (Adlard et al, 2008; Faux et al, 2010). Both scyllo-inositol (Transition Therapeutics and Elan) and PBT2 (Prana Biotechnology) are currently in clinical trials.…”

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

“…SEN1576 also protected the SH-SY5Y neuronal cell line following exposure to Aβ 1-42 , IC 50 = 23 μM [IC 50 = 26 μM for SEN1500 (O'Hare et al, 2013)]. Experimental parameters for the parent compound, RS-0406, have been described previously (O'Hare et al, 2010), showing ∼35% inhibition at 10 μM in the thioflavin-T assay and ∼40% protection at 40 μM in the MTT assay. The pharmacokinetic data obtained in rats (Table 1) show that following oral administration, SEN1576 was well absorbed and penetrated the brain.…”

“…Investigation of the effects of SEN1576 relative to memory in freely moving intact animals employed the ALCR operant schedule of food reinforcement. This procedure has been shown to be highly sensitive to adverse effects on memory induced by psychopharmacological manipulations (Weldon et al, 1996), and has been used extensively in contemporary models of dementia research involving experimental animals (e.g., Cleary et al, 2005;Townsend et al, 2006;Poling et al, 2008;O'Hare et al, 2010), we investigated the effects of orally administered SEN1576 treatment following i.c.v. 7PA2 CM injections in the rat.…”

“…injection of 7PA2 CM disrupts memory for learned behaviour in the rat (Cleary et al, 2005), and this original finding has been consistently confirmed (e.g., Townsend et al, 2006;Poling et al, 2008). This work has also been expanded to demonstrate the protective effects of putative pharmacotherapies against 7PA2 CM-induced behavioural deterioration (Townsend et al, 2006;O'Hare et al, 2010). Consequently, the Aβ oligomer toxicity theory of fundamental processes relative to the development of dementia in AD has substantial support from the contemporary literature, and pharmacotherapies targeting these underlying mechanisms are of considerable scientific interest.…”

“…Non-peptide small molecule inhibitors of Aβ aggregation have proven difficult to develop and, of the few available compounds of this type, many are unsuitable for clinical application because of their biological profile, poor oral bioavailability, or short half-life (Amijee and Scopes, 2009). However, Nakagami et al, (2002) reported that the small molecule RS-0406 inhibited Aβ toxicity, RS-0406 was then shown to protect hippocampal neurons against Aβ 1-42 -induced cytotoxicity, to alleviate Aβ 1-42 -impaired LTP (Walsh et al, 2005b), and to arrest 7PA2 CM-induced behavioural deterioration (O'Hare et al, 2010). Unfortunately, RS-0406 is not orally bioavailable, and as such is not a realistic candidate for the clinical treatment of dementia in AD.…”