Members of the PrC-210 family of aminothiols, including PrC-211 and PrC-252, are shown to be highly effective in reducing ischemia-reperfusion injury in two preclinical models, including kidney transplant and myocardial infarct. PrC-210 is shown to be well tolerated, achieving up to 100% efficacy at 0.5MTD doses where there are no discernible rodent toxicities when systemically administered either by ORAL or IP routes. In what is likely the most important aspect of ischemia-reperfusion injury, at in vitro PrC-210 concentrations of 2-3 mM, the same PrC-210 concentrations which have been measured in IP or ORAL PrC-210 treated rodents, PrC-210 is 100% effective in preventing DNA damage in a direct ROS-scavenging assay. In the standard mouse kidney clamp/unclamp model of I-R kidney insult, all three of the aminothiols profoundly suppress (>；80%) the kidney caspase levels seen in no drug treated controls； BUN levels in the I-R kidney mice are likewise reduced by PrC-210 and its analogs. In the mouse myocardial infarct model, a highly significant reduction in cardiac muscle death was observed when PrC-210 was administered systemically coincident with a 40-minute ligation and release of an anterior coronary artery. Complementary, in vitro studies using primary, neonatal, mouse cardiomyocytes showed a highly significant reduction of hydrogen peroxide-induced cardiomyocyte killing by coincident administration of the PrC-210 family aminothiols. PrC-210 family aminothiols are shown to suppress ischemia-reperfusion-induced cell and organ toxicities in a number of settings, significantly including organ transplant and myocardial infarct.
