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Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors
journal contributionposted on 03.08.2018, 00:00 authored by AD Pehere, M Pietsch, M Gütschow, Paul NeilsenPaul Neilsen, DS Pedersen, S Nguyen, O Zvarec, MJ Sykes, DF Callen, AD Abell
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 b-strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azidoalkyne-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 b-strand geometry as shown by NMR spectroscopy, X-ray analysis, and molecular docking studies. © 2013 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.