First-in-class pan caspase inhibitor developed for the treatment of liver disease

J Med Chem. 2005 Nov 3;48(22):6779-82. doi: 10.1021/jm050307e.

Abstract

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

MeSH terms

  • Adult
  • Alanine Transaminase / blood
  • Animals
  • Apoptosis / drug effects
  • Aspartate Aminotransferases / blood
  • Biological Availability
  • Caspase 3
  • Caspase Inhibitors*
  • Cholestasis / drug therapy
  • Cholestasis / pathology
  • Clinical Trials, Phase I as Topic
  • Half-Life
  • Hepatitis C, Chronic / drug therapy
  • Hepatocytes / drug effects
  • Hepatocytes / pathology
  • Humans
  • Jurkat Cells
  • Liver / drug effects
  • Liver / pathology
  • Liver Diseases / drug therapy*
  • Liver Diseases / enzymology
  • Liver Diseases / etiology
  • Mice
  • Pentanoic Acids / chemical synthesis*
  • Pentanoic Acids / chemistry
  • Pentanoic Acids / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • 3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
  • Caspase Inhibitors
  • Pentanoic Acids
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3