Abstract
The introduction and the optimization of an alpha-amino substituent based on a series of alpha-hydroxy-beta-N-biaryl ether sulfonamide hydroxamates is described. The modification leads to a new series of MMP-2/MMP-9 inhibitors with enhanced inhibitory activities and improved ADME properties. An efficacy study on reducing the ischemia-induced brain edema in the rat transient middle cerebral artery occlusion (tMCAo) model is also demonstrated.
MeSH terms
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Amino Acids / chemistry*
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Animals
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Brain Edema / chemically induced
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Disease Models, Animal
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Drug Design
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Gelatinases / antagonists & inhibitors*
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Humans
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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 Inhibitors*
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Microsomes, Liver / drug effects
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Middle Cerebral Artery / drug effects
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Molecular Structure
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Pyrazines / chemical synthesis*
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Pyrazines / chemistry
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Pyrazines / pharmacology*
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Rats
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Stereoisomerism
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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 / pharmacology
Substances
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Amino Acids
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CGS 27023A
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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Pyrazines
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Sulfonamides
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Gelatinases