1451982-70-9Relevant articles and documents
E-64c-hydrazide: A lead structure for the development of irreversible cathepsinc inhibitors
Radzey, Hanna,Rethmeier, Markus,Klimpel, Dennis,Grundhuber, Maresa,Sommerhoff, Christian P.,Schaschke, Norbert
, p. 1314 - 1321 (2013/08/23)
CathepsinC 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 Asp1 residue, provides an anchoring point for the Nterminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c) (k2/Ki=140±5M-1s-1) is demonstrated to be a lead structure for the development of irreversible cathepsinC inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp1 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=56000±1700M-1s-1).
