3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins

Janina Schmitz; Anna-Madeleine Beckmann; Adela Dudic; Tianwei Li; Robert Sellier; Ulrike Bartz; Michael Gütschow

doi:10.1021/ml500238q

3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins

ACS Med Chem Lett. 2014 Aug 11;5(10):1076-81. doi: 10.1021/ml500238q. eCollection 2014 Oct 9.

Authors

Janina Schmitz¹, Anna-Madeleine Beckmann², Adela Dudic², Tianwei Li², Robert Sellier², Ulrike Bartz³, Michael Gütschow²

Affiliations

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

Nitrile-type inhibitors are known to interact with cysteine proteases in a covalent-reversible manner. The chemotype of 3-cyano-3-aza-β-amino acid derivatives was designed in which the N-cyano group is centrally arranged in the molecule to allow for interactions with the nonprimed and primed binding regions of the target enzymes. These compounds were evaluated as inhibitors of the human cysteine cathepsins K, S, B, and L. They exhibited slow-binding behavior and were found to be exceptionally potent, in particular toward cathepsin K, with second-order rate constants up to 52 900 × 10(3) M(-1) s(-1).

Keywords: Cysteine proteases; human cathepsins; nitrile inhibitors; β-amino acids.