| References: |
Emricasan (IDN-6556, PF-03491390) is a potent irreversible pan-caspase inhibitor.
in vitro: Three caspase inhibitors (IDN-8066, IDN-1965, and IDN-6556) effectively attenuated SEC apoptosis and caspase 3 activation. The most potent inhibitor, IDN-6556, reduced SEC apoptosis and caspase 3 activity by 55% and 94%, respectively. Prevention of SEC apoptosis byIDN-6556 was not reduced when this agent was administered only during the cold preservation period.
in vivo: In the mouse alpha-Fas model of liver injury, i.p. administration of IDN-6556 resulted in marked reduction of alanine aminotransferase (ALT), apoptosis, and caspase activities at a dose of 3 mg/kg. At this dose, IDN-6556 was also effective when given up to 2 h before alpha-Fas and as late as 4 h after alpha-Fas administration. In both the alpha-Fas and d-galactosamine/lipopolysaccharide (D-Gln/LPS) model, ED(50) values in the sub-milligram per kilogram range were established after a number of routes of administration (i.p., i.v., i.m., or p.o.), ranging from 0.04 to 0.38 mg/kg . IDN-6556 (20 mg/kg) given for 7 days post-transplant led to a significantly enhanced rate of diabetes reversal as compared to vehicle. In addition, mice receiving caspase inhibitor displayed improved glucose tolerance and graft survival at the 1-month point. |
