title: 3-Cyano-3-aza-β-amino Acid Derivatives as Inhibitors of Human Cysteine Cathepsins.
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).
authors.affiliation: 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.
authors.forename: Janina
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Anna-Madeleine
authors.initials: AM
authors.lastname: Beckmann
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Adela
authors.initials: A
authors.lastname: Dudic
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Li
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Sellier
authors.affiliation: Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg , von-Liebig-Strasse 20, D-53359 Rheinbach, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bartz
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
keywords: Cysteine proteases; human cathepsins; nitrile inhibitors; β-amino acids