Acta Pharmacologica Sinica (2009) 30: 259-269; doi: 10.1038/aps.2008.26; published online 26th January 2009

Aim: The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase (BACE-1) bearing hydroxyethylene (HE) framework.     

Methods: First, we designed the small library based on our previous work and rational analysis.  Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity.  We then used molecular modeling to explain the possible binding mode. 

Results: Thirteen new compounds (6-18) have been designed, synthesized and bioassayed.  Their structures were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra and optical rotation.  Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck.  The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. 

Conclusion: This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer’s disease.

Keywords: aspartyl protease β-secretase; hydroxyethylene; solid phase; biological evaluation; molecular modeling