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Research ArticleGASTROINTESTINAL, 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

Niel C. Hoglen, Long-Shiuh Chen, Craig D. Fisher, Brad P. Hirakawa, Todd Groessl and Patricia C. Contreras
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 634-640; DOI: https://doi.org/10.1124/jpet.103.062034
Niel C. Hoglen
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Long-Shiuh Chen
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Craig D. Fisher
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Brad P. Hirakawa
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Todd Groessl
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Patricia C. Contreras
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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 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.

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  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.062034.

  • ABBREVIATIONS: TNF, tumor necrosis factor; ALT, alanine aminotransferase; α-Fas, anti-Fas agonistic antibody; d-Gln/LPS, d-galactosamine/lipopolysaccharide; LPS, lipopolysaccharide; LC/MS/MS, liquid chromatography tandem mass spectrometry; rfu, relative fluorescence unit; MRT, mean residence time; UDPGA, uridine diphosphate-glucuronic acid; PAPS, 3′-phosphoadenosine-5′-phosphosulfate; AUC, area under the curve; DEVD-AMC, aspartyl-glutamyl-valinyl-aspartyl-aminomethylcoumarin; ZVAD-FMK, carbobenzyloxy-valinyl-alanyl-aspartyl-fluoromethylketone; IDN-6556, 3-{2-[(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino}-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid.

    • Received November 11, 2003.
    • Accepted January 21, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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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
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Research ArticleGASTROINTESTINAL, 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

Niel C. Hoglen, Long-Shiuh Chen, Craig D. Fisher, Brad P. Hirakawa, Todd Groessl and Patricia C. Contreras
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 634-640; DOI: https://doi.org/10.1124/jpet.103.062034

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Research ArticleGASTROINTESTINAL, 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

Niel C. Hoglen, Long-Shiuh Chen, Craig D. Fisher, Brad P. Hirakawa, Todd Groessl and Patricia C. Contreras
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 634-640; DOI: https://doi.org/10.1124/jpet.103.062034
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