Abstract
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Crystallography, X-Ray
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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 13
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Matrix Metalloproteinase Inhibitors*
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Mice
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Models, Molecular
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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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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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Sulfonamides
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Matrix Metalloproteinase 13
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Mmp13 protein, mouse