Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors

BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design bas...

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Veröffentlicht in:European journal of medicinal chemistry 2010-06, Vol.45 (6), p.2578-2590
Hauptverfasser: Choi, Soo-Jeong, Cho, Joong-Heui, Im, Isak, Lee, So-Deok, Jang, Ji-Yeon, Oh, Yu-Min, Jung, Yong-Keun, Jeon, Eun-Seok, Kim, Yong-Chul
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Sprache:eng
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Zusammenfassung:BACE-1 has been shown to be an attractive therapeutic target in Alzheimer's disease (AD). Using a 1,4-dihydropyridine (DHP) scaffold, we synthesized new inhibitors of BACE-1 by modifying the known BACE inhibitor 2 containing a hydroxyethylamine (HEA) motif. Using structure-based drug design based on computer-aided molecular docking, the isophthalamide ring of 2 was replaced with a 1,4-dihydropyridine ring as a brain-targeting strategy. Several of the new dihydropyridine derivatives were synthesized and their BACE-1-inhibitory activities were evaluated using a cell-based, reporter gene assay system that measures the cleavage of alkaline phosphatase (AP)-APP fusion protein by BACE-1. Most of the 1,4-DHP analogs showed BACE-1-inhibitory activities with IC 50 values in the range 8–30 μM, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors. [Display omitted]
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2010.02.046