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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Department of Pharmacology, Idun Pharmaceuticals Inc., San Diego, California

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 -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 -Fas and as late as 4 h after -Fas administration. In both the -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 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.

Address correspondence to: Dr. Niel C. Hoglen, Department of Pharmacology, Idun Pharmaceuticals, 9380 Judicial Dr., San Diego, CA 92121. E-mail: nhoglen{at}idun.com

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