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Synthesis and Extended Activity of Triazole‐Containing Macrocyclic Protease Inhibitors

2013; Wiley; Volume: 19; Issue: 24 Linguagem: Inglês

10.1002/chem.201204260

1521-3765

Ashok D. Pehere, Markus Pietsch, Michael Gütschow, Paul M. Neilsen, Daniel Sejer Pedersen, Steven Nguyen, Ondrej Zvarec, Matthew J. Sykes, David F. Callen, Andrew D. Abell,

Ubiquitin and proteasome pathways

Abstract Peptide‐derived protease inhibitors are an important class of compounds with the potential to treat a wide range of diseases. Herein, we describe the synthesis of a series of triazole‐containing macrocyclic protease inhibitors pre‐organized into a β‐strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azido–alkyne‐based aldehydes are also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards calpain II, cathepsin L and S, and the 20S proteasome chymotrypsin‐like activity. Some of the first examples of highly potent macrocyclic inhibitors of cathepsin S were identified. These adopt a well‐defined β‐strand geometry as shown by NMR spectroscopy, X‐ray analysis, and molecular docking studies.