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.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Administration, Oral
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Animals
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Biological Assay
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Cartilage / drug effects
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Cartilage / enzymology
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Cattle
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Dialysis
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase Inhibitors*
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Metalloendopeptidases / antagonists & inhibitors
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Mice
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Osteoarthritis / drug therapy
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Rats
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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
Substances
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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N-hydroxy-2-(4-methoxybenzenesulfonyl)-2-methyl-3-(4-(2-piperidin-1-ylethoxy)phenyl)propionamide
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Protease Inhibitors
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Sulfones
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ADAM Proteins
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Matrix Metalloproteinase 13
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Metalloendopeptidases
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Mmp13 protein, mouse
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Mmp13 protein, rat
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ADAM17 Protein