Abstract
Triaylsulfonamides were identified as novel anti-inflammatory agents, acting by inhibition of RANKL and TNFα signaling. Structure-activity studies led to the identification of compounds with in vitro potencies of <100 nM against J774 macrophages and osteoclasts, but with little activity against osteoblasts or hepatocytes (IC(50) >50 μM). A representative compound (4k, ABD455) was able to completely prevent inflammation in vivo in a prevention model and was highly effective at controlling inflammation in a treatment model.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Biphenyl Compounds / chemical synthesis*
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology
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Caco-2 Cells
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Disease Models, Animal
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Humans
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Molecular Structure
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RANK Ligand / metabolism
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Signal Transduction / drug effects
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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ABD455
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Anti-Inflammatory Agents
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Biphenyl Compounds
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RANK Ligand
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Sulfonamides
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Tumor Necrosis Factor-alpha