The novel antiallergy compound, 5-methoxy-3-(1-methylethoxy)-1-phenyl-N-1H-tetrazol-5-yl-1H- indole-2- carboxamide,
L-arginine salt (CI-949), inhibited mediator release from human basophilic leukocytes and from human chopped lung mast cells challenged with
anti-IgE. In leukocytes,
CI-949 was a more potent inhibitor of
leukotriene C4/D4 and
thromboxane B2 release (concentration of
drug that inhibits mediator release by 50% [IC50] 0.5 and 0.1 mumol/L, respectively) than of
histamine (IC50, 11.4 mumol/L) when
anti-IgE was the challenging stimulus. In human lung, inhibition of release of all three mediators occurred at approximately equal concentrations (IC50s for
histamine, 16.6 mumol/L; for
leukotriene C4/D4, 7.1 mumol/L; and for
thromboxane B2, 6.2 mumol/L). The inhibition of histamine release from basophils by
CI-949 was further characterized using a variety of stimuli. Challenge with
anti-IgE,
histamine-releasing factor derived from lymphocytes, N-formyl-L-methionyl-L-leucyl-
L-phenylalanine, and
concanavalin A revealed potent inhibition (IC50, 10 to 15 mumol/L).
CI-949 was less potent versus
calcium ionophore A23187,
phorbol myristate acetate (12-o-tetradecanoylphorbol-13-acetate), and C5a (IC50s, 30, 54, and 60 mumol/L, respectively). These results suggest that diverse pathways of cell activation-excitation coupling exist for different stimuli in basophils. Furthermore, the activity and potency of
CI-949 in inhibiting release of
histamine,
leukotrienes, and
thromboxane from both human basophils and mast cells suggest that the compound will be effective clinically for indications in which these mediators are implicated, including
asthma and
allergic rhinitis.