INHIBITION OF HISTAMINE, LEUKOTRIENE-C4/D4, AND THROMBOXANE-B2 RELEASE FROM HUMAN-LEUKOCYTES AND HUMAN CHOPPED LUNG MAST-CELLS BY THE ALLERGIC MEDIATOR RELEASE INHIBITOR, CI-949

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-mu-mol/L, respectively) than of histamine (IC50, 11.4-mu-mol/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-mu-mol/L; for leukotriene C4/D4, 7.1-mu-mol/L; and for thromboxane B2, 6.2-mu-mol/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-mu-mol/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-mu-mol/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.