Peptidomimetic β‑Secretase Inhibitors Comprising a Sequence of Amyloid‑β Peptide for Alzheimer’s Disease

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
β-secretase inhibitors with a fragment of amyloid-β 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 β-secretase 1 in relation to β-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.