2. Academic Validation
  3. BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells

BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells

  • J Pharmacol Exp Ther. 2016 Jun;357(3):554-61. doi: 10.1124/jpet.116.233155.
David J Lamb 1,  Stefan Lutz Wollin 2,  Andreas Schnapp 2,  Daniel Bischoff 2,  Klaus J Erb 2,  Thierry Bouyssou 2,  Bernd Guilliard 2,  Christine Strasser 2,  Eva Wex 2,  Sylvia Blum 2,  Eva Thaler 2,  Helga Nickel 2,  Oliver Radmacher 2,  Hannah Haas 2,  Jennifer L Swantek 2,  Don Souza 2,  Melissa Canfield 2,  Della White 2,  Mark Panzenbeck 2,  Mohammed A Kashem 2,  Mary Sanville-Ross 2,  Takeshi Kono 2,  Katherina Sewald 2,  Armin Braun 2,  Helena Obernolte 2,  Olga Danov 2,  Gerhard Schaenzle 2,  Georg Rast 2,  Gerd-Michael Maier 2,  Matthias Hoffmann 2
Affiliations

Affiliations

  • 1 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.
  • 2 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.).
PMID: 27048659 DOI: 10.1124/jpet.116.233155
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.

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