title: 2,6-Naphthyridines as potent and selective inhibitors of the novel protein kinase C isozymes.
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.
authors.affiliation: Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland. maurice.van_eis@novartis.com
authors.forename: Maurice J
authors.initials: MJ
authors.lastname: van Eis
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Evenou
authors.forename: Philipp
authors.initials: P
authors.lastname: Floersheim
authors.forename: Christoph
authors.initials: C
authors.lastname: Gaul
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Lauren
authors.initials: L
authors.lastname: Monovich
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rummel
authors.forename: Walter
authors.initials: W
authors.lastname: Schuler
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Stark
authors.forename: Andre
authors.initials: A
authors.lastname: Strauss
authors.forename: Anette
authors.initials: A
authors.lastname: von Matt
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Juergen
authors.initials: J
authors.lastname: Wagner
authors.forename: Nicolas
authors.initials: N
authors.lastname: Soldermann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004768:Enterotoxins / Q000633:toxicity; D007376:Interleukin-2 / Q000097:blood; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D004768:Enterotoxins; D007376:Interleukin-2; D007527:Isoenzymes; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; C031818:enterotoxin B, staphylococcal; D011493:Protein Kinase C