PT  - JOURNAL ARTICLE
AU  - Lamb, David J.
AU  - Wollin, Stefan Lutz
AU  - Schnapp, Andreas
AU  - Bischoff, Daniel
AU  - Erb, Klaus J.
AU  - Bouyssou, Thierry
AU  - Guilliard, Bernd
AU  - Strasser, Christine
AU  - Wex, Eva
AU  - Blum, Sylvia
AU  - Thaler, Eva
AU  - Nickel, Helga
AU  - Radmacher, Oliver
AU  - Haas, Hannah
AU  - Swantek, Jennifer L.
AU  - Souza, Don
AU  - Canfield, Melissa
AU  - White, Della
AU  - Panzenbeck, Mark
AU  - Kashem, Mohammed A.
AU  - Sanville-Ross, Mary
AU  - Kono, Takeshi
AU  - Sewald, Katherina
AU  - Braun, Armin
AU  - Obernolte, Helena
AU  - Danov, Olga
AU  - Schaenzle, Gerhard
AU  - Rast, Georg
AU  - Maier, Gerd-Michael
AU  - Hoffmann, Matthias
TI  - BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells
AID  - 10.1124/jpet.116.233155
DP  - 2016 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 554--561
VI  - 357
IP  - 3
4099  - http://jpet.aspetjournals.org/content/357/3/554.short
4100  - http://jpet.aspetjournals.org/content/357/3/554.full
SO  - J Pharmacol Exp Ther2016 Jun 01; 357
AB  - 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. The lower potency in rat basophils was confirmed in both ex vivo inhibition of bronchoconstriction in precision-cut rat lung slices and in reversal of anaphylaxis-driven airway resistance in rats. The different cellular potencies translated into different in vivo efficacy; full efficacy in a rat ovalbumin model (that contains an element of mast cell dependence) was achieved with a trough plasma concentration of 340 nM, whereas full efficacy in a rat collagen-induced arthritis model (that contains an element of B-cell dependence) was achieved with a trough plasma concentration of 1400 nM. Taken together, these data provide a platform from which different estimates of human efficacious exposures can be made according to the relevant cell type for the indication intended to be treated.