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BI 1002494, a novel potent and selective oral spleen tyrosine kinase inhibitor, displays differential potency in human basophils and B cells

: Lamb, David J.; Wollin, Stefan Lutz; Schnapp, Andreas; Bischoff, Daniel; Erb, Klaus J.; Bouyssou, Thierry; Guilliard, Bernd; Strasser, Christine; Wex, Eva; Blum, Sylvia; Thaler, Eva; Nickel, Helga; Radmacher, Oliver; Haas, Hannah; Swantek, Jennifer L.; Souza, Don; Canfield, Melissa; White, Della; Panzenbeck, Mark; Kashem, Mohammed A.; Sanville-Ross, Mary; Kono, Takeshi; Sewald, Katherina; Braun, Armin; Obernolte, Helena; Danov, Olga; Schaenzle, Gerhard; Rast, Georg; Maier, Gerd-Michael; Hoffmann, Matthias


The journal of pharmacology and experimental therapeutics 357 (2016), No.3, pp.554-561
ISSN: 0022-3565
Journal Article
Fraunhofer ITEM ()
Rheumatoid-arthritis; Double-blind; Phase-III; inadequate response; parallel-group; Syk; inflammation; multicenter; Fostamatinib; discovery

BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, potent, and selective spleen tyrosine kinase (SYK) inhibitor with sustained plasma exposure after oral administration in rats, which qualifies this molecule as a good in vitro and in vivo tool compound. BI 1002494 exhibits higher potency in inhibiting high-affinity IgE receptor-mediated mast cell and basophil degranulation (IC50 = 115 nM) compared with B-cell receptor-mediated activation of B cells (IC50 = 810 nM). This may be explained by lower kinase potency when the physiologic ligand B-cell linker was used, suggesting that SYK inhibitors may exhibit differential potency depending on the cell type and the respective signal transduction ligand. A 3-fold decrease in potency was observed in rat basophils (IC50 = 323 nM) compared with human basophils, but a similar species potency shift was not observed in B cells.