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
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Adult
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Alanine Transaminase / blood
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Animals
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Apoptosis / drug effects
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Aspartate Aminotransferases / blood
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Biological Availability
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Caspase 3
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Caspase Inhibitors*
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Cholestasis / drug therapy
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Cholestasis / pathology
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Clinical Trials, Phase I as Topic
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Half-Life
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Hepatitis C, Chronic / drug therapy
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Hepatocytes / drug effects
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Hepatocytes / pathology
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Humans
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Jurkat Cells
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Liver / drug effects
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Liver / pathology
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Liver Diseases / drug therapy*
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Liver Diseases / enzymology
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Liver Diseases / etiology
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Mice
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Pentanoic Acids / chemical synthesis*
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Pentanoic Acids / chemistry
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Pentanoic Acids / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
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Caspase Inhibitors
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Pentanoic Acids
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Aspartate Aminotransferases
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Alanine Transaminase
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CASP3 protein, human
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Casp3 protein, mouse
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Casp3 protein, rat
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Caspase 3