Search

achieve this, selected changes to the heterocyclic nucleus, the linking atoms and the pendant aromatic rings were undertaken. Results: It is evident from this work that structure activity relationships exist around analogues of RS-0406 and that structural changes can result in significant improvements in its drug-like nature. We have discovered that modifications to the structure of RS-0406 have led to improvement in potency in both fibrillogenesis and cell viability assays. A new analogue, SEN1269, has been identified in which the central pyridazine ring has been replaced by a pyrimidine ring and an ether link was introduced along with the phenolic-OH replacement in one of the pendant aromatic rings. SEN1269 is more potent than RS-0406 and shows greater cell penetration, an improved in vitro ADME profile and absorption following oral dosing. In vivo, SEN1269 is also effective in rescuing the deficit in LTP caused by naturally-secreted oligomers of A . Furthermore, in an acute model of cognitive function in the rat using an alternating-lever cyclic-ratio paradigm, SEN1269 is effective in a dose-related manner in protecting against the deficit in cognitive behaviour induced by exogenously applied (ICV) naturally-secreted oligomers of A . Conclusions: SEN1269 represents a significant lead in the quest for a small molecule inhibitor of amyloid toxicity and supports the proposal that further evaluation of this chemical series is warranted.