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

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BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/04/05/jpet.116.233155.DC1 1521-0103/357/3/554–561$25.00 http://dx.doi.org/10.1124/jpet.116.233155 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:554–561, June 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics BI 1002494, a Novel Potent and Selective Oral Spleen Tyrosine Kinase Inhibitor, Displays Differential Potency in Human Basophils and B Cells s David J. Lamb, Stefan Lutz Wollin, Andreas Schnapp, Daniel Bischoff, Klaus J. Erb, Thierry Bouyssou, Bernd Guilliard, Christine Strasser, Eva Wex, Sylvia Blum, Eva Thaler, Helga Nickel, Oliver Radmacher, Hannah Haas, Jennifer L. Swantek, Don Souza, Melissa Canfield, Della White, Mark Panzenbeck, Mohammed A. Kashem, Mary Sanville- Ross, Takeshi Kono, Katherina Sewald, Armin Braun, Helena Obernolte, Olga Danov, Downloaded from Gerhard Schaenzle, Georg Rast, Gerd-Michael Maier, and Matthias Hoffmann 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 jpet.aspetjournals.org and Experimental Medicine, Hannover, Germany (K.S., A.B., H.O., O.D.) Received February 25, 2016; accepted March 31, 2016 ABSTRACT BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] a similar species potency shift was not observed in B cells. The napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one] is a novel, po- lower potency in rat basophils was confirmed in both ex vivo at ASPET Journals on September 30, 2021 tent, and selective spleen tyrosine kinase (SYK) inhibitor with inhibition of bronchoconstriction in precision-cut rat lung slices and sustained plasma exposure after oral administration in rats, in reversal of anaphylaxis-driven airway resistance in rats. The which qualifies this molecule as a good in vitro and in vivo tool different cellular potencies translated into different in vivo efficacy; compound. BI 1002494 exhibits higher potency in inhibiting high- full efficacy in a rat ovalbumin model (that contains an element of affinity IgE receptor–mediated mast cell and basophil degranula- mast cell dependence) was achieved with a trough plasma tion (IC50 5 115 nM) compared with B-cell receptor–mediated concentration of 340 nM, whereas full efficacy in a rat collagen- activation of B cells (IC50 5 810 nM). This may be explained by induced arthritis model (that contains an element of B-cell de- lower kinase potency when the physiologic ligand B-cell linker was pendence) was achieved with a trough plasma concentration of used, suggesting that SYK inhibitors may exhibit differential 1400 nM. Taken together, these data provide a platform from potency depending on the cell type and the respective signal which different estimates of human efficacious exposures can be transduction ligand. A 3-fold decrease in potency was observed in made according to the relevant cell type for the indication intended rat basophils (IC50 5 323 nM) compared with human basophils, but to be treated. Introduction 2010), primarily expressed in hematopoietic tissues but also in a variety of different tissues (Yanagi et al., 2001). SYK Spleen tyrosine kinase (SYK) is a member of the Syk family propagates signal transduction for a number of immunore- of nonreceptor cytoplasmic tyrosine kinases (Riccaboni et al., ceptor tyrosine-based activation motif–dependent proinflam- matory pathways, including Fc receptor, B-cell receptor This research was supported by Boehringer Ingelheim Pharma GmbH & Co. (BCR), and integrin signaling (Riccaboni et al., 2010). The KG and Boehringer Ingelheim Pharmaceuticals, Inc. dx.doi.org/10.1124/jpet.116.233155. proximal location of SYK in these multiple pathways confers a s This article has supplemental material available at jpet.aspetjournals.org. broad range of anti-inflammatory activity and makes SYK an ABBREVIATIONS: BAY 61-3606, 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide dihydrochloride; BCR, B-cell receptor; BI 1002494, (R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6]napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one; BLNK, B-cell linker; BSA, bovine serum albumin; CIA, collagen-induced arthritis; DMSO, dimethylsulfoxide; DNP, dinitroprusside; Fc«R1, high-affinity IgE receptor; GS-9973, 2-[[(1R,2S)-2-aminocyclohexyl] amino]-4-[3-(triazol-2-yl)anilino]pyrimidine-5-carboxamide; hERG, human ether-a-go-go–related gene potassium channel; JAK, Janus kinase; OVA, ovalbumin; PAK, p21-activated kinase; PBS, phosphate-buffered saline; PCLS, precision-cut lung slice; PK, pharmacokinetics; PRT062070, 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide; PRT062607, 2-[[(1R,2S)-2-aminocyclohexyl]amino]-4-[3-(triazol- 2-yl)anilino]pyrimidine-5-carboxamide; R343, 5,7-dibromoquinolin-8-ol; R406, 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl- 4H-pyrido[3,2-b][1,4]oxazin-3-one; R788, 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl] methyl dihydrogen phosphate; SYK, spleen tyrosine kinase; TAK-659, diethyl 2-dimethoxyphosphinothioylsulfanylbutanedioate. 554 SYK Inhibitor with Differential Cellular Pharmacology 555 attractive therapeutic target for a range of inflammatory of 10 nM on human basophils (Yamamoto et al., 2003). diseases. For example, the early and late allergic responses However, the poor rodent pharmacokinetics (PK) profile observed in asthma and other atopic diseases can be directly required very high doses to achieve an inhibitory effect in linked to the degranulation of mast cells that have been vivo (Yamamoto et al., 2003; Bhagwat, 2009). More recently, sensitized with allergen-specific IgE binding to the high- Merck published a very potent advancement on the more affinity IgE receptor (Fc«R1) (Allan et al., 2012). SYK is selective Portola compound structure (SYK kinase IC50 5 immediately downstream of Fc«R1, and inhibition of SYK has 60 pM, whole blood basophil IC50 5 58 nM) with which only been shown to abrogate these responses (Wex et al., 2011). zeta chain–associated protein kinase 70 in the 265-kinase B-cell activity has been linked to other inflammatory diseases, panel was inhibited within 100-fold of the SYK IC50 (Ellis such as rheumatoid arthritis, where they may present antigen et al., 2015). to T cells or secrete proinflammatory cytokines and rheuma- For respiratory diseases, the SYK inhibitor R343 (5,7- toid factor (Panayi, 2005), and in which the B-cell–depleting dibromoquinolin-8-ol) from Rigel Pharmaceuticals has been antibody rituximab has been shown to be clinically effective evaluated using the inhalation route in clinical trials in (Cohen et al., 2006). SYK is also downstream of BCR, and codevelopment with Pfizer, showing complete inhibition of inhibition of SYK has been shown to inhibit BCR-mediated both the early and late atopic phases after allergen challenge activation of B cells (Braselmann et al., 2006). in individuals with mild asthma (Allan et al., 2012). However, Because of this broad mechanism of action, several SYK in a small 42-kinase panel, 12 kinases (29% of the kinase inhibitors are currently in clinical development but all seem panel) were inhibited with a higher potency than SYK and 13 Downloaded from to be hampered by some liabilities. Fostamatinib [R406 (6- additional kinases (32% of the kinase panel) within 20% of [[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]- SYK activity (Ramis et al., 2015), again suggesting that a large 2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one); Rigel proportion of the kinome may be inhibited. Recently, Almirall Pharmaceuticals, South San Francisco, CA) has been evalu- reported that another inhaled SYK inhibitor (LAS189386, ated in clinical trials for rheumatoid arthritis in codevelopment 1-{2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]pyridin-4-yl}- with AstraZeneca; however, fostamatinib failed in one of the N-pyrazin-2-yl-1H-indazol-3-amine) shows preclinical activity jpet.aspetjournals.org two coprimary phase III efficacy endpoints (Genovese et al., in rodent models of ovalbumin (OVA)–induced early asthmatic 2014; Weinblatt et al., 2014) and is currently in development for response (Ramis et al., 2015), although this compound exhibits immune thrombocytopenia and IgA-mediated nephropathy. only limited selectivity for SYK, with 7 other kinases (17% of the Recent analysis suggests that the soluble prodrug of R406, kinase panel) being inhibited within 20% of SYK activity in a R788 ([6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl] short 42-kinase selectivity panel. amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl We report here a novel potent and selective SYK inhibitor, dihydrogen phosphate)] (Braselmann et al., 2006), has a Kd BI 1002494 [(R)-4-{(R)-1-[7-(3,4,5-trimethoxy-phenyl)-[1,6] at ASPET Journals on September 30, 2021 within 10-fold of the Kd for SYK for 110 of 440 kinases napthyridin-5-yloxy]-ethyl}pyrrolidin-2-one], with sustained (including FMS-related tyrosine kinase 3, lymphocyte cell- plasma exposure in rodents after oral administration, which specific protein tyrosine kinase, Janus kinases JAK1 and exhibits enhanced potency in basophils/mast cells versus JAK3, and c-kit), suggesting that more than 20% of the kinome B cells and displays an excellent in vitro–ex vivo–in vivo may be inhibited by R406 within 10-fold of the concentration potency translation.
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