Abstract
A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
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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Carboxylic Acids / chemistry
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Cell Line
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology*
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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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
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Tryptophan / analogs & derivatives*
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Tryptophan / chemical synthesis
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Tryptophan / chemistry
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Tryptophan / pharmacology
Substances
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2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid
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Carboxylic Acids
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Enzyme Inhibitors
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Sulfonamides
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Tryptophan
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ADAM Proteins
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ADAM17 Protein