ABSTRACT
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , ADAM Proteins , ADAM17 Protein , Administration, Oral , Animals , Biological Assay , Cartilage/drug effects , Cartilage/enzymology , Cattle , Dialysis , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 13 , Metalloendopeptidases/antagonists & inhibitors , Mice , Osteoarthritis/drug therapy , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Piperidines/chemical synthesis , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , ADAM Proteins , ADAM17 Protein , Administration, Oral , Animals , Binding Sites , Biological Assay , Cartilage/drug effects , Cartilage/enzymology , Cattle , Crystallography, X-Ray , Dialysis , Dogs , Haplorhini , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Male , Matrix Metalloproteinase 13 , Matrix Metalloproteinases/chemistry , Metalloendopeptidases/antagonists & inhibitors , Mice , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rabbits , Rats , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
A series of benzodiazepine inhibitors of the MMPs and TACE has been developed. These compounds display an interesting selectivity profile and should be useful tools for exploring the biological relevance of such selectivity.
Subject(s)
Benzodiazepines/pharmacology , Hydroxamic Acids , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Pyrazines , ADAM Proteins , ADAM17 Protein , Benzodiazepines/chemical synthesis , Cartilage/drug effects , Cartilage/enzymology , Indicators and Reagents , Protease Inhibitors/chemical synthesis , Structure-Activity Relationship , SulfonamidesABSTRACT
Contractility studies in isolated feline myocytes have demonstrated that sphingosine, a metabolite stimulated by tumor necrosis factor (TNF) binding, decreases intracellular calcium release and depresses inotropic activity. This study investigated the electrophysiologic effects of sphingosine in isolated cat myocytes as well as the cardiodynamic consequence of TNF, sphingosine, and its metabolic precursors in vivo. In cat myocytes, sphingosine markedly decreased action potential duration, lowered action potential plateau, and inhibited L-type calcium current (I(Ca-L)). After administration of TNF, sphingomyelin, C2-ceramide, or sphingosine, only C2-ceramide and sphingosine depressed cardiac function in normal rats. Negative inotropic effects of C2-ceramide were attenuated by N-oleoylethanolamine (NOE), a ceramidase inhibitor that blocks sphingosine formation. Rats pretreated with NOE before undergoing 30 min of acute regional myocardial ischemia followed by 150 min of reperfusion exhibited improved survival. Most deaths could be attributed to acute pump failure accompanied by bradycardia. Myocardial infarct size and peak serum TNF were not different between NOE- and vehicle-treated groups (3,908 +/- 1097 pg/ml and 3,027 +/- 846 pg/ml, respectively). These results indicate that sphingosine exerts direct inhibitory effects on the action potential and I(Ca-L) in isolated feline myocytes, consistent with previously reported sphingosine activity on I(Ca-L) in isolated rat myocytes. The in vivo study suggests that reducing sphingosine production with N-oleoylethanolamine attenuates cardiodepression and can improve overall survival after ischemic injury. Clearly, agents that modulate sphingosine production limit cardiodepression and may provide a therapeutic benefit in clinical conditions of myocardial inflammatory injury.
