Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
Eur J Med Chem. 2010 May;45(5):2089-94. doi: 10.1016/j.ejmech.2010.01.044. Epub 2010 Jan 28.
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.
基于 OM99-2 的结构和其与β-分泌酶复合物的 X 射线晶体结构，设计了一系列含有 Leu*Ala 羟亚乙基等排物作为可切割键替代物的化合物。合成了 31 个化合物，并测定了它们对β-分泌酶的抑制活性。结果发现，在我们的靶化合物中，异丁基是作为 C 末端更好的 R3 取代基，而 4-硝基苄基是最佳的 R2 侧链。借助分子建模，比较了化合物 9 和 22 与β-分泌酶的结合模式。结果表明，22 与β-分泌酶的结合模式比 9 更强。这表明该系列肽拟似物抑制剂的最佳长度为 P3-P2'。具有这种长度的化合物的分子量约为 600。
