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ACS Med Chem Lett. 2015 Dec 28;7(3):211-6. doi: 10.1021/acsmedchemlett.5b00474. eCollection 2016 Mar 10.

Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry.

Author information

1
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Strasse 20, D-53359 Rheinbach, Germany.
2
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
3
Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg , von-Liebig-Strasse 20, D-53359 Rheinbach, Germany.

Abstract

An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited K i values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models.

KEYWORDS:

Copper-catalyzed azide−alkyne cycloaddition; cysteine proteases; human cathepsin B; nitrile inhibitors

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