| Autor: |
Cha M, Kim S, Jung E, Cho I, Park I, Yoon S; Department of Integrative Biotechnology & Translational Medicine, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea., Ye S, Lee S, Kim J, Kim HY, Oh JH; College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea., Maeng HJ; College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea., Kim I, Kim Y; Department of Integrative Biotechnology & Translational Medicine, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea.; Amyloid Solution, Seongnam-si 13486, Gyeonggi-do, Republic of Korea.; Department of Psychiatry, Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. |
| Abstrakt: |
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. |
