Synthesis and γ-secretase activity of APP substrate-based hydroxyethylene dipeptide isosteres

Two new APP substrate-based hydroxyethylene isosteres (AT and VI) were prepared and their dipeptide conjugates shown not to inhibit the γ-secretase-mediated formation of either Aβ1-40 or Aβ1-42. The FG isostere and a des-hydroxy hydroxyethylene isostere also gave inactive compounds. Conversely, a number of compounds containing the intact substrate-unrelated Phe-Phe (FF) hydroxyethylene isostere were shown to be potent inhibitors (ED50=14–732 nM). These results show that the factors governing the substrate-based design of γ-secretase inhibitors are more complicated than first thought.