Abstract
Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.
MeSH terms
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Arthritis, Rheumatoid / drug therapy
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Combinatorial Chemistry Techniques
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Drug Design
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HSP27 Heat-Shock Proteins / antagonists & inhibitors
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HSP27 Heat-Shock Proteins / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Leukocytes, Mononuclear / drug effects
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Lipopolysaccharides / pharmacology
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Molecular Structure
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Monocytes / drug effects
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Phosphorylation
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacology*
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
Substances
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Cytokines
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HSP27 Heat-Shock Proteins
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Pyrimidinones
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Pyrroles
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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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p38 Mitogen-Activated Protein Kinases