RT Journal Article
SR Electronic
T1 BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 554
OP 561
DO 10.1124/jpet.116.233155
VO 357
IS 3
A1 Lamb, David J.
A1 Wollin, Stefan Lutz
A1 Schnapp, Andreas
A1 Bischoff, Daniel
A1 Erb, Klaus J.
A1 Bouyssou, Thierry
A1 Guilliard, Bernd
A1 Strasser, Christine
A1 Wex, Eva
A1 Blum, Sylvia
A1 Thaler, Eva
A1 Nickel, Helga
A1 Radmacher, Oliver
A1 Haas, Hannah
A1 Swantek, Jennifer L.
A1 Souza, Don
A1 Canfield, Melissa
A1 White, Della
A1 Panzenbeck, Mark
A1 Kashem, Mohammed A.
A1 Sanville-Ross, Mary
A1 Kono, Takeshi
A1 Sewald, Katherina
A1 Braun, Armin
A1 Obernolte, Helena
A1 Danov, Olga
A1 Schaenzle, Gerhard
A1 Rast, Georg
A1 Maier, Gerd-Michael
A1 Hoffmann, Matthias
YR 2016
UL http://jpet.aspetjournals.org/content/357/3/554.abstract
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.