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2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes

Van Eis, Maurice and Evenou, Jean-Pierre and Floersheim, Philipp and Gaul, Christoph and Jacob, Sandra and Monovich, Lauren and Rummel, Gabriele and Schuler, Walter and Stark, Wilhelm and Strauss, Andre and Von Matt, Anette and Vangrevelinghe, Eric and Wagner, Juergen and Soldermann, Nicolas (2011) 2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes. Bioorganic & Medicinal Chemistry Letters, 21 (24). pp. 7367-7372. ISSN 0960-894X

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 alpha, betaI, delta, epsilon, eta and theta (in particular PKCdelta, epsilon, eta and theta), and display a 10-100 fold selectivity over the classical PKC isotypes. The prototype compound 11 was found to inhibit PKCtheta-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.

Item Type: Article
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Keywords: Protein Kinase C Inhibitors Isozyme specific 2,6-Naphthyridines T cell inhibition
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2745

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