Abstract
Potent and selective inhibition of matrix metalloproteinases was demonstrated for a series of sulfonamide-based hydroxamic acids. The design of the heterocyclic sulfonamides incorporates a six- or seven-member central ring with a P2' substituent that can be modified. Binding interactions of this substituent at the S2' site are believed to contribute to high inhibitory potency against stromelysin, collagenase-3 and gelatinases A and B, and to provide selectivity against collagenase-1 and matrilysin. An X-ray structure of a stromelysin inhibitor complex was obtained to provide insights into the SAR and selectivity trends observed for the series.
MeSH terms
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Collagenases
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / pharmacology
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Heterocyclic Compounds, 1-Ring / chemical synthesis
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Heterocyclic Compounds, 1-Ring / pharmacology*
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Inhibitory Concentration 50
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Macromolecular Substances
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase Inhibitors*
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Sensitivity and Specificity
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / pharmacology*
Substances
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Enzyme Inhibitors
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Heterocyclic Compounds, 1-Ring
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Macromolecular Substances
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Matrix Metalloproteinase Inhibitors
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Sulfonamides
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Collagenases
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Matrix Metalloproteinase 13
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collagenase 1