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E-64c-hydrazide: A Lead Structure for the Development of Irreversible Cathepsin C Inhibitors

E-64c-hydrazide: A Lead Structure for the Development of Irreversible Cathepsin C Inhibitors

Hanna Radzey, Markus Rethmeier, Dennis Klimpel, Maresa Grundhuber, Christian P Sommerhoff, Norbert Schaschke

ChemMedChem. 2013 Aug;8(8):1314-21.

PMID: 23780739

Abstract:

Cathepsin C is a papain-like cysteine protease with dipeptidyl aminopeptidase activity that is thought to activate various granule-associated serine proteases. Its exopeptidase activity is structurally explained by the so-called exclusion domain, which blocks the active-site cleft beyond the S2 site and, with its Asp 1 residue, provides an anchoring point for the N terminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c) (k2/Ki =140±5 M(-1) s(-1)) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp 1 residue at the entrance of the S2 pocket by hydrogen bonding while also occupying the flat hydrophobic S1'-S2' area with its leucine-isoamylamide moiety. Furthermore, structure-activity relationship studies revealed that functionalization of this distal amino group with alkyl residues can be used to occupy the conserved hydrophobic S2 pocket. In particular, the n-butyl derivative was identified as the most potent inhibitor of the series (k2/Ki =56 000±1700 M(-1) s(-1)).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP76684894	E-64c		76684-89-4	Price

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