Peptidomimetic beta-Secretase Inhibitors Comprising a Sequence of Amyloid-beta Peptide for Alzheimer's Disease

摘要

Alzheimer's disease is a grave social problem in an aging population. A major problem is the passage of drugs through the blood brain barrier. This work tests the hypothesis that the conjugation of peptidomimetic beta-secretage inhibitors with a fragment of amyloid-beta peptide facilitates entrance into the central nervous system. HVR-3 (compound 4), one of the conjugation products, was found to be as potent as OM00-3, a known peptidomimetic inhibitor, 4-fold more selective toward beta-secretase 1 in relation to beta-secretase 2 and 3-fold more resistant to in vitro metabolization in human serum. Its intravenous administration to mice and Wistar rats generated an active metabolite recovered from the rodent's brains.