Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer’s Disease

Previously,
we reported that immunoproteasome (iP)-targeting linear
peptide epoxyketones improve cognitive function in mouse models of
Alzheimer’s disease (AD) in a manner independent of amyloid
β. However, these compounds’ clinical prospect for AD
is limited due to potential issues, such as poor brain penetration
and metabolic instability. Here, we report the development of iP-selective
macrocyclic peptide epoxyketones prepared by a ring-closing metathesis
reaction between two terminal alkenes attached at the P2 and P3/P4
positions of linear counterparts. We show that a lead macrocyclic
compound DB-60 (20) effectively inhibits the catalytic
activity of iP in ABCB1-overexpressing cells (IC50: 105
nM) and has metabolic stability superior to its linear counterpart.
DB-60 (20) also lowered the serum levels of IL-1α
and ameliorated cognitive deficits in Tg2576 mice. The results collectively
suggest that macrocyclic peptide epoxyketones have improved CNS drug
properties than their linear counterparts and offer promising potential
as an AD drug candidate.