Abstract
Novel 1-(2-aminopyrazin-3-yl)methyl-2-thioureas are described as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). These compounds demonstrate potent in vitro activity against the enzyme with IC(50) values as low as 15 nM, and suppress expression of TNFalpha in THP-1 cells and in vivo in an acute inflammation model in mice. The synthesis, structure-activity relationship (SAR), and biological evaluation of these compounds are discussed.
MeSH terms
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Animals
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Cell Line, Tumor
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Drug Evaluation, Preclinical
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Humans
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Inflammation / drug therapy
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Inhibitory Concentration 50
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Mice
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Structure-Activity Relationship
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Thiourea / chemistry*
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Thiourea / pharmacology
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Thiourea / therapeutic use
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Tumor Necrosis Factor-alpha / drug effects
Substances
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Tumor Necrosis Factor-alpha
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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Thiourea