Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity

Document Type

Article

Publication Date

3-28-2013

Abstract

Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that degrades insulin and the amyloid ß-protein and is strongly implicated in the pathogenesis of diabetes and Alzheimer's disease. We recently developed the first effective inhibitors of IDE, peptide hydroxamates that, while highly potent and selective, are relatively large (MW > 740) and difficult to synthesize. We present here a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds. Through the generation of truncated variants, we identified a compound with significantly reduced size (MW = 455.5) that nonetheless retains good potency (ki = 78 ± 11 nM) and selectivity for IDE. Notably, the potency of these inhibitors was found to vary as much as 60-fold in a substrate-specific manner, an unexpected finding for active site-directed inhibitors. Collectively, our findings demonstrate that potent, small-molecule IDE inhibitors can be developed that, in certain instances, can be highly substrate selective. © 2013 American Chemical Society.

Publication Title

Journal of Medicinal Chemistry

Volume

56

Issue

6

First Page

2246

Last Page

2255

Digital Object Identifier (DOI)

10.1021/jm301280p

PubMed ID

23437776

ISSN

00222623

E-ISSN

15204804

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