Abstract
Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.
MeSH terms
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Animals
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Cells, Cultured
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Graft Rejection / prevention & control*
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Humans
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Lymphocyte Activation / drug effects*
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Macaca fascicularis
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Mice
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Mice, Inbred BALB C
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Psoriasis / drug therapy*
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Pyrroles / chemistry
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Pyrroles / pharmacokinetics
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Pyrroles / therapeutic use*
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Quinazolines / chemistry
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Quinazolines / pharmacokinetics
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Quinazolines / therapeutic use*
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Rats
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Protein Kinase Inhibitors
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Pyrroles
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Quinazolines
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sotrastaurin
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Protein Kinase C