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

Based on the structure of OM99-2 and the X-ray crystal structure of its complex with β-secretase, a series of compounds containing the Leu*Ala hydroxyethylene isostere as a scissile bond substitution were designed. 31 compounds were synthesized and their β-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 β-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.

31 Compounds containing the Leu*Ala hydroxyethylene isostere as a scissile bond substitution were designed, synthesized and evaluated with their β-secretase inhibition activities. It was found that isobutyl group was a better R3 substitution as C-terminus, 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 β-secretase were compared.Figure optionsDownload as PowerPoint slide