title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Idun Pharmaceuticals Inc., San Diego, CA 92121, USA. nhoglen@idun.com
authors.forename: Niel C
authors.initials: NC
authors.lastname: Hoglen
authors.forename: Long-Shiuh
authors.initials: LS
authors.lastname: Chen
authors.forename: Craig D
authors.initials: CD
authors.lastname: Fisher
authors.forename: Brad P
authors.initials: BP
authors.lastname: Hirakawa
authors.forename: Todd
authors.initials: T
authors.lastname: Groessl
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Contreras
mesh_terms: D000818:Animals; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010421:Pentanoic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010421:Pentanoic Acids