Abstract
Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Amino Acids / chemical synthesis
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Animals
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Binding Sites
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Crystallography, X-Ray
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Heterocyclic Compounds, 4 or More Rings / chemical synthesis
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Heterocyclic Compounds, 4 or More Rings / chemistry*
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / metabolism
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Isoquinolines / chemistry
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Ketones / chemical synthesis
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Ketones / chemistry
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Ketones / pharmacology
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Lactams / chemical synthesis
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Lactams / chemistry
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Lactams / pharmacology
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Mice
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrroles / chemistry
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Amino Acids
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Heterocyclic Compounds, 4 or More Rings
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Intracellular Signaling Peptides and Proteins
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Isoquinolines
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Ketones
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Lactams
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Protein Kinase Inhibitors
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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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isoquinoline