Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks Aß-Fibrinogen Interaction and Aß-Induced Contact System Activation.

ABSTRACT

Accumulating evidence suggests that fibrinogen, a key protein in the coagulation cascade, plays an important role in circulatory dysfunction in Alzheimer's disease (AD). Previous work has shown that the interaction between fibrinogen and ß-amyloid (Aß), a hallmark pathological protein in AD, induces plasmin-resistant abnormal blood clots, delays fibrinolysis, increases inflammation, and aggravates cognitive function in mouse models of AD. Since Aß oligomers have a much stronger affinity for fibrinogen than Aß monomers, we tested whether amyloid aggregation inhibitors could block the Aß-fibrinogen interaction and found that some Aß aggregation inhibitors showed moderate inhibitory efficacy against this interaction. We then modified a hit compound so that it not only showed a strong inhibitory efficacy toward the Aß-fibrinogen interaction but also retained its potency toward the Aß42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated Aß42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the Aß-fibrinogen interaction and Aß aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as Aß aggregation-driven pathology in AD.