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
Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.
Subject(s)
Caspase Inhibitors , Cell Death/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Ketones/pharmacology , Animals , Aspartic Acid/chemistry , Cells, Cultured , Heterocyclic Compounds/chemical synthesis , Ketones/chemical synthesis , Mice , Models, Biological , Naphthols/chemistry , Structure-Activity Relationship , Valine/chemistryABSTRACT
Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.
Subject(s)
Benzimidazoles/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepines/therapeutic use , Brain Ischemia/drug therapy , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Benzimidazoles/chemistry , Benzodiazepines/chemistry , Binding Sites , Caco-2 Cells , Diabetes Mellitus, Experimental/drug therapy , Drug Design , Enzyme Inhibitors/chemistry , Humans , Mice , Models, Molecular , Rats , 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.
