Synthesis and preliminary evaluation of peptidomimetic inhibitors of human beta-secretase

Eur J Med Chem. 2010 May;45(5):2089-94. doi: 10.1016/j.ejmech.2010.01.044. Epub 2010 Jan 28.

Abstract

Based on the structure of OM99-2 and the X-ray crystal structure of its complex with beta-secretase, a series of compounds containing the Leu*Ala hydroxyethylene isostere as a scissile bond substitution were designed. 31 compounds were synthesized and their beta-secretase inhibition activities were measured. It was found that isobutyl group was a better R3 substitution as C-terminus in our target compounds, and 4-nitrobenzyl group was the best R2 side chain. With the aid of molecular modeling, the binding modes of compounds 9 and 22 with beta-secretase were compared. The result revealed a stronger bonding mode of 22 than 9. This explored that the optimal length of this series of peptidomimetic inhibitors was P3-P2'. The molecular weights of compounds with this length are around 600.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Ethylenes / chemical synthesis*
  • Ethylenes / chemistry
  • Ethylenes / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Ethylenes
  • hydroxyethylene
  • Amyloid Precursor Protein Secretases