Synthesis and Extended Activity of Triazole‐Containing Macrocyclic Protease Inhibitors. Issue 24 (18th April 2013)

• Record Type: Journal Article
• Authors: Pehere, Ashok D.; Pietsch, Markus; Gütschow, Michael; Neilsen, Paul M.; Pedersen, Daniel Sejer; Nguyen, Steven; Zvarec, Ondrej; Sykes, Matthew J.; Callen, David F.; Abell, Andrew D.
• Is Part Of: Chemistry. Volume 19:Issue 24(2013)
• Page Start: 7975
• Page End: 7981
• Publication Date: 2013-04-18
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201204260
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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.</p> </abstract>