Potent inhibition of calcium mobilization and mast cell activation by the pyrazole derivative BTP2 (86.9)

Abstract

Abstract Cytosolic Ca2+ changes in mast cells are central for driving their activation. Thus, pharmacological tools that inhibit this process represent unique strategies for inhibiting mast cell function. We find that the pyrazole compound BTP2 inhibited FcϵRI-triggered sustained Ca2+ influx in a mast cell-like cell line RBL-2H3 with little effect on the tyrosine phosphorylation of cellular proteins. It also did not affect FcϵRI-induced phosphorylation of mitogen-activated protein kinases Erk1/2, JNK, and p38 nor downstream c-fos expression. This suggests that BTP2 inhibits Ca2+ mobilization without affecting the FcϵRI signal transduction cascade. BTP2 inhibited degranulation and β-hexosaminidase release in RBL-2H3 cells. Consistent with this effect, BTP2 inhibited antigen-induced histamine release in vivo. BTP2 also inhibited cytokine secretion of IL-2, IL-3, IL-4, IL-13, and TNF-α by BMMCs. Analysis of structure-function relationships between the BTP2 parent compound and its derivatives implicate a role for the trifluoromethyl group at both carbon positions 3 and 5 of pyrazole in the inhibition of degranulation of RBL-2H3 cells, with a more dominant effect evoked by the trifluoromethyl group at C3. In conclusion, our studies indicate that pyrazole compounds can provide the molecular framework for the design of specific inhibitors of Ca2+ entry mechanisms and further BTP2 as a medicinal candidate for the treatment of allergic reactions and other mast cell-mediated diseases.