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

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.

Compound 11 potently inhibits the novel PKC isozymes δ, ε, η, θ, with IC50 values of 20, 5, 5 and 77 nM, respectively, and displays a 11–180-fold selectivity over the classical PKC isotypes α/β.Figure optionsDownload as PowerPoint slide