Aminopyrimidine Class Aggregation Inhibitor Effectively Blocks A beta-Fibrinogen Interaction and A beta-Induced Contact System Activation

作者：Singh Pradeep K; Kawasaki Masanori; Berk Rauch Hanna E; Nishida Goushi; Yamasaki Takeshi; Foley Michael A; Norris Erin H; Strickland Sidney; Aso Kazuyoshi^*; Ahn Hyung Jin^*

来源：Biochemistry, 2018, 57(8): 1399-1409.

DOI：10.1021/acs.biochem.7b01214

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 beta-amyloid (A beta), 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 A beta oligomers have a much stronger affinity for fibrinogen than A beta monomers, we tested whether amyloid aggregation inhibitors could block the A beta-fibrinogen interaction and found that some A beta 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 A beta-fibrinogen interaction but also retained its potency toward the A beta 42 aggregation inhibition process. Furthermore, our best hit compound, TDI-2760, modulated A beta 42-induced contact system activation, a pathological condition observed in some AD patients, in addition to inhibiting the A beta-fibrinogen interaction and A beta-aggregation. Thus, TDI-2760 has the potential to lessen vascular abnormalities as well as A beta aggregation-driven pathology in AD.

• 出版日期2018-2-27