1. 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.
- Author
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Cha M, Kim S, Jung E, Cho I, Park I, Yoon S, Ye S, Lee S, Kim J, Kim HY, Oh JH, Maeng HJ, Kim I, and Kim Y
- Subjects
- Animals, Mice, Chalcone chemistry, Chalcone pharmacology, Chalcone analogs & derivatives, Chalcones chemistry, Chalcones pharmacology, Chalcones administration & dosage, Male, Brain drug effects, Brain metabolism, Humans, Memory drug effects, Protein Aggregates drug effects, Blood-Brain Barrier metabolism, Blood-Brain Barrier drug effects, Maze Learning drug effects, Pyridines chemistry, Pyridines pharmacology, Pyridines administration & dosage, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Disease Models, Animal, Mice, Transgenic
- Abstract
The aberrant assembly of amyloid-β (Aβ) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aβ-targeted immunotherapy reinforce the notion that clearing Aβ burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aβ 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-Aβ functional assays, Aβ aggregation prevention and Aβ aggregate clearance, we selected YIAD-0336, ( E )-8-((1 H -pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2- b ]quinolin-9(6 H )-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aβ 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 Aβ 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 Aβ aggregates is a promising therapeutic approach for AD.
- Published
- 2024
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