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Bioorg Med Chem Lett. 2003 Jan 6;13(1):37-41.

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

Author information

  • 1Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. alan_nadin@merck.com

Abstract

Two new APP substrate-based hydroxyethylene isosteres (AT and VI) were prepared and their dipeptide conjugates shown not to inhibit the gamma-secretase-mediated formation of either Abeta1-40 or Abeta1-42. 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 (ED(50)=14-732 nM). These results show that the factors governing the substrate-based design of gamma-secretase inhibitors are more complicated than first thought.

PMID:
12467612
[PubMed - indexed for MEDLINE]
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