Abstract
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.
Original language | English (US) |
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Pages (from-to) | 2578-2590 |
Number of pages | 13 |
Journal | European Journal of Medicinal Chemistry |
Volume | 45 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2010 |
Externally published | Yes |
Keywords
- 1,4-Dihydropyridine
- Alzheimer's disease
- BACE-1 inhibitors
- Hydroxyethylamine
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry