2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes
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Van Eis, Maurice, Evenou, Jean-Pierre, Floersheim, Philipp, Gaul, Christoph, Jacob, Sandra, Monovich, Lauren, Rummel, Gabriele, Schuler, Walter, Stark, Wilhelm, Strauss, Andre, Von Matt, Anette, Vangrevelinghe, Eric, 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 |