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

Soo Jeong Choi, Joong Heui Cho, Isak Im, So Deok Lee, Ji Yeon Jang, Yu Min Oh, Yong Keun Jung, Eun Seok Jeon, Yong Chul Kim

Research output: Contribution to journalArticle


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 languageEnglish (US)
Pages (from-to)2578-2590
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Issue number6
StatePublished - Jun 1 2010
Externally publishedYes


  • 1,4-Dihydropyridine
  • Alzheimer's disease
  • BACE-1 inhibitors
  • Hydroxyethylamine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Choi, S. J., Cho, J. H., Im, I., Lee, S. D., Jang, J. Y., Oh, Y. M., Jung, Y. K., Jeon, E. S., & Kim, Y. C. (2010). Design and synthesis of 1,4-dihydropyridine derivatives as BACE-1 inhibitors. European Journal of Medicinal Chemistry, 45(6), 2578-2590.