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.
Subject(s)
Caspase Inhibitors , Liver Diseases/drug therapy , Pentanoic Acids/chemical synthesis , Adult , Alanine Transaminase/blood , Animals , Apoptosis/drug effects , Aspartate Aminotransferases/blood , Biological Availability , Caspase 3 , 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/enzymology , Liver Diseases/etiology , Mice , Pentanoic Acids/chemistry , Pentanoic Acids/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.
Subject(s)
Caspase Inhibitors , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Apoptosis/drug effects , Carbamates , Cell Line , Humans , Inhibitory Concentration 50 , Kinetics , Neurodegenerative Diseases/drug therapy , Stroke/drug therapy , Structure-Activity RelationshipABSTRACT
A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.
