Abstract
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Acetylene / chemistry*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Hydroxamic Acids / chemistry
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Metalloendopeptidases / antagonists & inhibitors*
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Molecular Structure
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Structure-Activity Relationship
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Sulfonamides / chemistry
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ortho-Aminobenzoates / chemistry*
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ortho-Aminobenzoates / pharmacology
Substances
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Enzyme Inhibitors
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Hydroxamic Acids
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Sulfonamides
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ortho-Aminobenzoates
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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Acetylene