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

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.