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

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Abstract

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.

The synthesis and γ-secretase activity of a number of hydroxyethylene isosteres is reported.

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Acknowledgements

We thank Drs. Jules Shafer and Steve Gardell (Merck Research Laboratories, West Point) for their interest in this work and Dr. Ute Gerhard for NOE measurements.24

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