Abstract
New kinase inhibitors can be found by synthesis of targeted arrays of compounds designed using system-based knowledge as well as through screening focused or diverse compounds. Most array strategies aim to add functionality to a fragment that binds in the purine subpocket of the ATP-site. Here, an alternative pharmacophore-guided array approach is described which set out to discover novel purine subpocket-binding groups. Results are shown for p38alpha and cFMS kinase, for which multiple distinct series with nanomolar potency were discovered. Some of the compounds showed potency in cell-based assays and good pharmacokinetic properties.
MeSH terms
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Adenosine Triphosphate / chemistry
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacokinetics*
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Animals
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Heterocyclic Compounds, 1-Ring / chemical synthesis*
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Heterocyclic Compounds, 1-Ring / chemistry
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Heterocyclic Compounds, 1-Ring / pharmacokinetics*
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Inhibitory Concentration 50
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Rats
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Structure-Activity Relationship
Substances
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Amides
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Heterocyclic Compounds, 1-Ring
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Protein Kinase Inhibitors
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Adenosine Triphosphate
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Mitogen-Activated Protein Kinase 14