Abstract
The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemical synthesis
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology
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Binding Sites
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Caco-2 Cells
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Cell Membrane Permeability / drug effects
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Drug Design
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Humans
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / metabolism
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Mice
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Molecular Docking Simulation
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Protein Binding
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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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Protein Structure, Tertiary
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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Thiophenes / chemistry*
Substances
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Anti-Inflammatory Agents
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BX795
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Protein Kinase Inhibitors
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Pyrimidines
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Thiophenes
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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I-kappa B Kinase