Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo[2,3-b:4,5-b′]dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model

초록

The aberrant assembly of amyloid-beta (A beta) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of A beta-targeted immunotherapy reinforce the notion that clearing A beta burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of A beta aggregates, we synthesized 51 novel polyfunctionalized furo[2,3-b:4,5-b ']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-A beta functional assays, A beta aggregation prevention and A beta aggregate clearance, we selected YIAD-0336, (E)-8-((1H-pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3 ',2 ':4,5]furo[3,2-b]quinolin-9(6H)-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated A beta directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed A beta plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of A beta aggregates is a promising therapeutic approach for AD.

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