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Synthesis and Extended Activity of Triazole‐Containing Macrocyclic Protease Inhibitors
Author(s) -
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.
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201204260
Subject(s) - peptidomimetic , protease , chemistry , stereochemistry , triazole , combinatorial chemistry , cathepsin , calpain , proteases , peptide , enzyme , biochemistry , organic chemistry
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.