Inhibitors Designed for Presenilin 1 by Means of Aspartic Acid Activation. Preliminary Communication

✍ Scribed by Gregor Larbig; Andrea Zall; Boris Schmidt

• Book ID: 102258353
• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: German
• Weight: 168 KB
• Volume: 87
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.200490208

✦ Synopsis

Abstract

γ‐Secretase, a multiprotein aspartic protease crucial to Alzheimer's dementia, is not available for NMR experiments and has, so far, escaped crystallization. A positional scan of the aspartic protease by reactive probes may provide the necessary structural information for drug development. We describe here the synthesis of acid‐labile compounds based on the known inhibitor DAPT (1), e.g., the N‐terminally functionalized diazo compound 4 or the C‐terminally acid‐labile (cyclopropylmethyl)ester 11, which were designed to react in the specific acidic active‐site environment of the aspartic protease presenilin 1. The acid‐labile DAPT analogues 11–13, indeed, displayed strong inhibition in a cell‐free γ‐secretase assay.