ABSTRACT
Inhibition of FBPase is considered a promising way to reduce hepatic gluconeogenesis and therefore could be a potential approach to treat type 2 diabetes. Herein we report the discovery of a series of purine phosphonic acids as AMP mimics targeting the AMP site of FBPase, which was achieved using a structure-guided drug design approach. These non-nucleotide purine analogues inhibit FBPase in a similar manner and with similar potency as AMP. More importantly, several purine analogues exhibited potent cellular and in vivo glucose-lowering activities, thus achieving proof-of-concept for inhibiting FBPase as a drug discovery target. For example, compounds 4.11 and 4.13 are as equipotent as AMP with regard to FBPase inhibition. Furthermore, compound 4.11 inhibited glucose production in primary rat hepatocytes and significantly lowered blood glucose levels in fasted rats.
Subject(s)
Adenosine Monophosphate/metabolism , Biomimetics , Fructose-Bisphosphatase/antagonists & inhibitors , Organophosphonates/chemistry , Organophosphonates/pharmacology , Purines/chemistry , Administration, Oral , Animals , Biological Availability , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Fructose-Bisphosphatase/chemistry , Fructose-Bisphosphatase/metabolism , Glucose/metabolism , Humans , Inhibitory Concentration 50 , Liver/enzymology , Organophosphonates/pharmacokinetics , Organophosphonates/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Substrate SpecificityABSTRACT
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.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , 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.
