Abstract
The present study describes a novel series of ATP-competitive PKC inhibitors based on the 2,6-naphthyridine template. Example compounds potently inhibit the novel Protein Kinase C (PKC) isotypes δ, ε, η, θ (in particular PKCε/η, and display a 10-100-fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCθ-dependent pathways in vitro and in vivo. In vitro, a-CD3/a-CD28-induced lymphocyte proliferation could be effectively blocked in 10% rat whole blood. In mice, 11 dose-dependently inhibited Staphylococcus aureus enterotoxin B-triggered IL-2 serum levels after oral dosing.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Computer Simulation
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Crystallography, X-Ray
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Enterotoxins / toxicity
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Interleukin-2 / blood
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Mice
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Naphthyridines / chemical synthesis
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Naphthyridines / chemistry*
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Naphthyridines / pharmacokinetics
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase C / 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 Structure, Tertiary
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Rats
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
Substances
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Enterotoxins
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Interleukin-2
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Isoenzymes
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Naphthyridines
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Protein Kinase Inhibitors
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enterotoxin B, staphylococcal
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Protein Kinase C