Chemically Driven Clearance of Amyloid Aggregates by Polyfunctionalized Furo2,3-b:4,5-b'dipyridine-Chalcone Hybrids to Ameliorate Memory in an Alzheimer Mouse Model

• Published in: Molecular pharmaceutics 2024-07, Vol.21 (7), p.3330
• Main Authors: Cha, Minhae, Kim, Sunmi, Jung, Euijin, Cho, Illhwan, Park, InWook, Yoon, Soljee, Ye, Suhyun, Lee, Songmin, Kim, JiMin, Kim, Hye Yun, Oh, Ji-Hoon, Maeng, Han-Joo, Kim, Ikyon, Kim, YoungSoo
• Format: Article
• Language: English
• ISSN: 1543-8392; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.4c00068

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-((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 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.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-((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 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 dis