Lamb, David J.David J.LambWollin, Stefan LutzStefan LutzWollinSchnapp, AndreasAndreasSchnappBischoff, DanielDanielBischoffErb, Klaus J.Klaus J.ErbBouyssou, ThierryThierryBouyssouGuilliard, BerndBerndGuilliardStrasser, ChristineChristineStrasserWex, EvaEvaWexBlum, SylviaSylviaBlumThaler, EvaEvaThalerNickel, HelgaHelgaNickelRadmacher, OliverOliverRadmacherHaas, HannahHannahHaasSwantek, Jennifer L.Jennifer L.SwantekSouza, DonDonSouzaCanfield, MelissaMelissaCanfieldWhite, DellaDellaWhitePanzenbeck, MarkMarkPanzenbeckKashem, Mohammed A.Mohammed A.KashemSanville-Ross, MaryMarySanville-RossKono, TakeshiTakeshiKonoSewald, KatherinaKatherinaSewaldBraun, ArminArminBraunObernolte, HelenaHelenaObernolteDanov, OlgaOlgaDanovSchaenzle, GerhardGerhardSchaenzleRast, GeorgGeorgRastMaier, Gerd-MichaelGerd-MichaelMaierHoffmann, MatthiasMatthiasHoffmann2022-03-052022-03-052016https://publica.fraunhofer.de/handle/publica/24638110.1124/jpet.116.233155BI 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.enRheumatoid-arthritisDouble-blindPhase-IIIinadequate responseparallel-groupSykinflammationmulticenterFostamatinibdiscovery615journal article