ABSTRACT
Aryl sulfonamide-based endothelin antagonists were synthesized and covalently linked to the reactive lysine of the m38C2 antibody to create a series of CovX-Bodies. These chemically programmed antibodies behaved as potent endothelin receptor antagonists in vitro and had antitumor efficacy in a prostate cancer xenograft model which, on a molar basis, far exceeded the activity of the parent small molecule.
Subject(s)
Antibodies/chemistry , Antibodies/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Receptors, Endothelin/drug effects , Animals , CHO Cells , Cricetinae , Cricetulus , Endothelin A Receptor Antagonists , Endothelin B Receptor Antagonists , Humans , Indicators and Reagents , Mice , Mice, Nude , Molecular Conformation , Neoplasm Transplantation , Structure-Activity RelationshipABSTRACT
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
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
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.
