TY - JOUR T1 - Characterization of IDN-6556 (3-{2-(2-<em>tert</em>-Butyl-phenylaminooxalyl)-amino]-propionylamino}-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic Acid): a Liver-Targeted Caspase Inhibitor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 634 LP - 640 DO - 10.1124/jpet.103.062034 VL - 309 IS - 2 AU - Niel C. Hoglen AU - Long-Shiuh Chen AU - Craig D. Fisher AU - Brad P. Hirakawa AU - Todd Groessl AU - Patricia C. Contreras Y1 - 2004/05/01 UR - http://jpet.aspetjournals.org/content/309/2/634.abstract N2 - 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 α-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 α-Fas and as late as 4 h after α-Fas administration. In both the α-Fas and d-galactosamine/lipopolysaccharide (d-Gln/LPS) model, ED50 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 t1/2 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 t1/2, indicating a significant first-pass effect. Liver concentrations remained constant after oral administration for at least a 4-h period, reaching a Cmax 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. The American Society for Pharmacology and Experimental Therapeutics ER -