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.
|Number of pages||17|
|Journal||Journal of Medicinal Chemistry|
|State||Published - Aug 12 2021|
Bibliographical noteFunding Information:
The authors thank the National Institutes of Health (R01 CA188354 to K.B.K. and R01 GM111084 to S.L.), the National Research Foundation of Korea (2017R1E1A1A01074656 to D-E.K. and MRC2017R A5A2015541 to J.T.H), and the Creative-Pioneering Researchers Program through Seoul National University (to W.L.) for financially supporting this work.
© 2021 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery