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E‐64c‐Hydrazide: A Lead Structure for the Development of Irreversible Cathepsin C Inhibitors
Author(s) -
Radzey Hanna,
Rethmeier Markus,
Klimpel Dennis,
Grundhuber Maresa,
Sommerhoff Christian P.,
Schaschke Norbert
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300093
Subject(s) - chemistry , hydrazide , stereochemistry , moiety , cathepsin c , active site , exopeptidase , cysteine , serine , cathepsin , cathepsin b , residue (chemistry) , cathepsin o , biochemistry , amino acid , enzyme , organic chemistry
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 (2 S ,3 S )‐ trans ‐epoxysuccinyl‐ L ‐leucylamido‐3‐methylbutane (E‐64c) ( k 2 / K i =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 ( k 2 / K i =56 000±1700 M −1 s −1 ).