Abstract
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Animals
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Crystallography, X-Ray
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Humans
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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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In Vitro Techniques
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Matrix Metalloproteinase Inhibitors*
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Metalloendopeptidases / antagonists & inhibitors*
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Mice
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Models, Molecular
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Molecular Structure
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Monocytes / drug effects
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Monocytes / metabolism
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Oxidation-Reduction
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology
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Structure-Activity Relationship
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacology
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
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Sulfoxides / chemical synthesis*
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Sulfoxides / chemistry
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Sulfoxides / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Hydroxamic Acids
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Matrix Metalloproteinase Inhibitors
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Piperidines
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Sulfides
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Sulfones
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Sulfoxides
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Tumor Necrosis Factor-alpha
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse