The potency, efficacy, and pharmacokinetic properties of
IDN-6556 (3-[2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic
acid), a first-in-class
caspase inhibitor in clinical trials for the treatment of
liver diseases, were characterized in vivo in rodent models. 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. Efficacy was also demonstrated in the rat D-Gln/LPS model with 67 and 72% reductions in ALT activities after i.p. and p.o. treatment with
IDN-6556 (10 mg/kg), respectively. Pharmacokinetic analysis in the rat demonstrated rapid clearance after i.v., i.p., and s.c. administration with terminal t(1/2) ranging from 46 to 51 min. Low absolute bioavailability after p.o. administration was seen (2.7-4%), but portal
drug concentrations after
oral administration were 3-fold higher than systemic concentrations with a 3.7-fold increase in the terminal t(1/2), indicating a significant first-pass effect. Liver concentrations remained constant after
oral administration for at least a 4-h period, reaching a C(max) of 2558 ng/g liver at 120 min. Last, 51 +/- 20 and 4.9 +/- 3.4% of
IDN-6556 was excreted intact in bile after i.v. and p.o. administration, respectively. This evaluation indicates that
IDN-6556 has marked efficacy in models of
liver disease after
oral administration and thus, is an excellent candidate for the treatment of
liver diseases characterized by excessive apoptosis.