Abstract
We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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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 / pharmacokinetics
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Binding Sites
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Computer Simulation
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Crystallography, X-Ray
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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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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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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Anti-Inflammatory Agents
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Pyrimidines
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Tumor Necrosis Factor-alpha
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2,4-diaminopyrimidine
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases