Abstract
Matrix metalloproteinase-9 (MMP-9) has been implicated in the breakdown of the blood-brain barrier during cerebral ischemia. As a result, inhibition of MMP-9 may have utility as a therapeutic intervention in stroke. Towards this end, we have synthesized a series of 1-hydroxy-2-pyridinones that have excellent in vitro potency in inhibiting MMP-9 in addition to MMP-2. Representative compounds also demonstrate good efficacy in the mouse transient mid-cerebral artery occlusion (tMCAO) model of cerebral ischemia.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Brain Ischemia / drug therapy*
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Disease Models, Animal
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Inhibitory Concentration 50
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Male
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Matrix Metalloproteinase Inhibitors*
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology
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Pyridones / chemical synthesis*
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Pyridones / chemistry
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Pyridones / pharmacokinetics
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Pyridones / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Zinc / chemistry
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Zinc / metabolism
Substances
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Pyridones
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Sulfonamides
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Zinc