2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes |
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Authors: | van Eis Maurice J Evenou Jean-Pierre Floersheim Philipp Gaul Christoph Cowan-Jacob Sandra W Monovich Lauren Rummel Gabriele Schuler Walter Stark Wilhelm Strauss Andre von Matt Anette Vangrevelinghe Eric Wagner Juergen Soldermann Nicolas |
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Affiliation: | aNovartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland;bNovartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA |
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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. |
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Keywords: | Protein Kinase C Inhibitors Isozyme specific 2,6-Naphthyridines T cell inhibition |
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