Abstract
A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.
MeSH terms
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Collagenases / chemistry*
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Crystallography, X-Ray
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Drug Design
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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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Indicators and Reagents
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Kinetics
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Matrix Metalloproteinase 8
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Matrix Metalloproteinase Inhibitors*
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Models, Molecular
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemistry
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Phenylalanine / pharmacology
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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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Structure-Activity Relationship
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Succinates / chemical synthesis
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Succinates / chemistry
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Succinates / pharmacology
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry*
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Thiophenes / pharmacology
Substances
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Hydroxamic Acids
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Indicators and Reagents
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Succinates
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Thiophenes
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Phenylalanine
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batimastat
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Collagenases
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Matrix Metalloproteinase 8