title: BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells.
abstract: 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.
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.) david.lamb@boehringer-ingelheim.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lamb
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Stefan Lutz
authors.initials: SL
authors.lastname: Wollin
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnapp
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Bischoff
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Erb
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Thierry
authors.initials: T
authors.lastname: Bouyssou
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Bernd
authors.initials: B
authors.lastname: Guilliard
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Christine
authors.initials: C
authors.lastname: Strasser
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Eva
authors.initials: E
authors.lastname: Wex
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Sylvia
authors.initials: S
authors.lastname: Blum
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Eva
authors.initials: E
authors.lastname: Thaler
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Helga
authors.initials: H
authors.lastname: Nickel
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Oliver
authors.initials: O
authors.lastname: Radmacher
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Hannah
authors.initials: H
authors.lastname: Haas
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Swantek
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Don
authors.initials: D
authors.lastname: Souza
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Melissa
authors.initials: M
authors.lastname: Canfield
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Della
authors.initials: D
authors.lastname: White
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Mark
authors.initials: M
authors.lastname: Panzenbeck
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Kashem
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Mary
authors.initials: M
authors.lastname: Sanville-Ross
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kono
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Katherina
authors.initials: K
authors.lastname: Sewald
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Armin
authors.initials: A
authors.lastname: Braun
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Helena
authors.initials: H
authors.lastname: Obernolte
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Olga
authors.initials: O
authors.lastname: Danov
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schaenzle
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Georg
authors.initials: G
authors.lastname: Rast
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Gerd-Michael
authors.initials: GM
authors.lastname: Maier
authors.affiliation: Immunology and Respiratory Research (D.J.L., S.L.W., A.S., K.J.E., T.B., B.G., C.S., E.W., S.B., E.T., H.N., O.R., H.H.), Discovery Drug Support (D.B., G.S., G.R., G.-M.M.), and Medicinal Chemistry (M.H.), Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; Immunology and Respiratory Research (J.L.S., D.S., M.C., D.W., M.P.) and Small Molecule Discovery Research (M.A.K., M.S.-R.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Chuo-ku, Kobe City, Japan (T.K.); and Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology*; D001491:Basophils / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D000072377:Syk Kinase / Q000037:antagonists & inhibitors*
chemical_list: C000619117:BI 1002494; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D011760:Pyrrolidinones; D000072377:Syk Kinase