Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors

TY - JOUR

T1 - Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors

AU - Pehere, A.D.

AU - Pietsch, M.

AU - Gütschow, M.

AU - Zvarec, O.

AU - Neilsen, P.M.

AU - Pedersen, Daniel Sejer

AU - Nguyen, S.

AU - Zvarec, O.

AU - Sykes, M.J.

AU - Callen, D.F.

AU - Abell, A. D.

PY - 2013/6/10

Y1 - 2013/6/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84878547453&partnerID=8YFLogxK

U2 - 10.1002/chem.201204260

DO - 10.1002/chem.201204260

M3 - Journal article

C2 - 23606616

AN - SCOPUS:84878547453

SN - 0947-6539

VL - 19

SP - 7975

EP - 7981

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 24

ER -