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. Epub 2016 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / enzymology*
  • Basophils / drug effects*
  • Basophils / enzymology*
  • Humans
  • Male
  • Mast Cells / drug effects
  • Mast Cells / enzymology
  • Naphthyridines / administration & dosage
  • Naphthyridines / pharmacology*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / pharmacology*
  • Pyrrolidinones / administration & dosage
  • Pyrrolidinones / pharmacology*
  • Rats
  • Syk Kinase / antagonists & inhibitors*

Substances

  • BI 1002494
  • Naphthyridines
  • Protein Kinase Inhibitors
  • Pyrrolidines
  • Pyrrolidinones
  • Syk Kinase