E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors

Radzey H, Rethmeier M, Klimpel D, Grundhuber M, Sommerhoff CP, Schaschke N (2013)
Chemmedchem 8(8): 1314-1321.

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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 Asp1 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) (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 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 (k(2)/K-i=56000 +/- 1700 M-1 s(-1)).
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Radzey H, Rethmeier M, Klimpel D, Grundhuber M, Sommerhoff CP, Schaschke N. E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem. 2013;8(8):1314-1321.
Radzey, H., Rethmeier, M., Klimpel, D., Grundhuber, M., Sommerhoff, C. P., & Schaschke, N. (2013). E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem, 8(8), 1314-1321.
Radzey, H., Rethmeier, M., Klimpel, D., Grundhuber, M., Sommerhoff, C. P., and Schaschke, N. (2013). E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem 8, 1314-1321.
Radzey, H., et al., 2013. E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem, 8(8), p 1314-1321.
H. Radzey, et al., “E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors”, Chemmedchem, vol. 8, 2013, pp. 1314-1321.
Radzey, H., Rethmeier, M., Klimpel, D., Grundhuber, M., Sommerhoff, C.P., Schaschke, N.: E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors. Chemmedchem. 8, 1314-1321 (2013).
Radzey, Hanna, Rethmeier, Markus, Klimpel, Dennis, Grundhuber, Maresa, Sommerhoff, Christian P., and Schaschke, Norbert. “E-64c-Hydrazide: A Lead Structure for the Development of Irreversible CathepsinC Inhibitors”. Chemmedchem 8.8 (2013): 1314-1321.
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