Abstract
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, 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 / antagonists & inhibitors*
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ADAM17 Protein
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Animals
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Biological Availability
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Caspase Inhibitors
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Cell Line
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Crystallography, X-Ray
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Cysteine Proteinase Inhibitors / chemical synthesis*
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Cysteine Proteinase Inhibitors / pharmacokinetics
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Cysteine Proteinase Inhibitors / pharmacology
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Dogs
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Humans
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Hydroxamic Acids / chemical synthesis*
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Hydroxamic Acids / pharmacokinetics
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Hydroxamic Acids / pharmacology
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Inhibitory Concentration 50
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Lipopolysaccharides / pharmacology
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Mice
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Molecular Structure
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Monocytes
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Rats
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Species Specificity
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / drug effects
Substances
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Hydroxamic Acids
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Lipopolysaccharides
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Sulfonamides
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Tumor Necrosis Factor-alpha
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse
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Adam17 protein, rat