Abstract
A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.
MeSH terms
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Administration, Oral
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Amino Acids / chemistry
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Animals
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Benzofurans / chemistry
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Cartilage / drug effects
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Cartilage / enzymology
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Cattle
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Chelating Agents / chemistry
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Collagenases / chemistry
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Collagenases / metabolism
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Crystallography, X-Ray
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Drug Design
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In Vitro Techniques
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Inhibitory Concentration 50
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase Inhibitors*
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Models, Molecular
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Protease Inhibitors / administration & dosage
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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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Protein Structure, Tertiary
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Rats
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Sensitivity and Specificity
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Structure-Activity Relationship
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Substrate Specificity
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Zinc / metabolism
Substances
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Amino Acids
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Benzofurans
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Chelating Agents
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Collagenases
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Matrix Metalloproteinase 13
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Mmp13 protein, rat
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Zinc
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benzofuran