کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1397750 | 1501188 | 2010 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors](/preview/png/1397750.png)
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 IC50 values in the range 8–30 μM, suggesting that the 1,4-DHP skeleton may be utilized to develop brain-targeting BACE-1 inhibitors.
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Journal: European Journal of Medicinal Chemistry - Volume 45, Issue 6, June 2010, Pages 2578–2590