Abstract
A series of cyclopropyl hydroxamic acids were prepared. Many of the compounds displayed picomolar affinity for the TACE enzyme while maintaining good to excellent selectivity profiles versus MMP-1, -2, -3, -7, -14, and ADAM-10. X-ray analysis of an inhibitor in the TACE active site indicated that the molecules bound to the enzyme in the S1'-S3' pocket.
MeSH terms
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ADAM Proteins / antagonists & inhibitors*
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ADAM17 Protein
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Animals
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Area Under Curve
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Biological Availability
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Drug Discovery
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacokinetics
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Hydroxamic Acids / pharmacology*
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Models, Molecular
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Rats
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Rats, Sprague-Dawley
Substances
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Hydroxamic Acids
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Protease Inhibitors
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ADAM Proteins
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ADAM17 Protein
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Adam17 protein, rat