The t-1/2 of plasma E-64c is 0.48 hours. The hemodynamic effects of E-64c are absent at this dose. Using two way analysis of variance, the effects of reperfusion (p=0.0016) or E-64c (p=0.0226) per se on infarct size are significant. In comparing Group A with Group B and Group C with Group D, the depletion of CPK in the E-64c treated groups (Groups A and C) is slightly less than in the vehicle-injected groups (Groups B and D). The insufficient effect of E-64c alone may be explained by the early administration and relatively short t-1/2. Since the effectiveness of NCO-700 has been established,6),7) our findings might indicate a small but beneficial effect of E-64c on infarct size and CPK content[2].
In Vitro
E-64c, a derivative of naturally occurring epoxide inhibitor of cysteine proteases, with papain; especially with regard to the hydrogen bonding and hydrophobic interactions of the ligands with conserved residues in the catalytic binding site[1]. E 64c (k2/Ki=140±5M-1s-1) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors[3].
Kinase Assay
Cell Assay
Animal Administration
Dogs[2] Studies are carried out in 83 mongrel dogs with a mean weight of 11.2kg. They are anesthetized with intravenous sodium thiamylal (7mg/kg). An intravenous bolus of E-64c (100mg/kg), dissolved in saturated sodium bicarbonate, is administered immediately before the occlusion and after reperfusion in Group A (n=17), whereas Group B (n=17) receive only the vehicle solution at these times. In the remaining 49 dogs (Groups C and D), the LAD is permanently ligated at the same level and an intravenous bolus of either Loxistatin acid (100mg/kg) (Group C; n=24) or vehicle only (Group D; n=25) is given immediately before and 1 hour after the ligation. The dose of E-64c is designed for its possible use in clinical practice and the estimated intramyocardial Loxistatin acid molecular concentration is 1,000 times that of total mCANP[2].
References
[1]. Khan MS, et al. Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors. PLoS One. 2013 Aug 5;8(8):e69982.
[2]. Toda G, et al. Calcium-activated neutral protease inhibitor (E-64c) and reperfusion for experimental myocardial infarction. Jpn Heart J. 1989 May;30(3):375-86.
[3]. Radzey H, et al. E-64c-hydrazide: a lead structure for the development of irreversible cathepsin C inhibitors. ChemMedChem. 2013 Aug;8(8):1314-21.
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