Abstract
A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Aminopyridines / chemistry*
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Aminopyridines / pharmacology*
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Binding Sites
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Cell Degranulation / drug effects
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Cell Line
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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 / chemistry
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Intracellular Signaling Peptides and Proteins / metabolism
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Mast Cells / drug effects*
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Mast Cells / enzymology
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Mast Cells / physiology
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / metabolism
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Syk Kinase
Substances
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Aminopyridines
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase