Characterization of IDN-6556 (3-{2-(2-tert-Butyl-phenylaminooxalyl)-amino]-propionylamino}-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic Acid): a Liver-Targeted Caspase Inhibitor

• Published in: The Journal of pharmacology and experimental therapeutics 2004-05, Vol.309 (2), p.634-640
• Main Authors: Hoglen, Niel C, Chen, Long-Shiuh, Fisher, Craig D, Hirakawa, Brad P, Groessl, Todd, Contreras, Patricia C
• Format: Article
• Language: English
• Subjects: Animals; Caspase Inhibitors; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Male; Mice; Mice, Inbred BALB C; Models, Animal; Pentanoic Acids - blood; Pentanoic Acids - pharmacokinetics; Pentanoic Acids - pharmacology; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.062034

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, 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.