CI-922 — A novel, potent antiallergic compound — I. Inhibition of mediator release in vitro

CI-922 (3,7-dimethoxy-4-phenyl- N-1 H-tetrazol-5-yl-4 H-furol[3,2- b]-indole-2-carboxamide, L-arginine salt) is a novel antiallergy compound which inhibits the release of the inflammatory mediators histamine and leukotriene (LT) from stimulated cells. CI-922 showed potent, effective inhibition of antigen-induced mediator release from human basophils and isolated guinea pig lung. The drug inhibited ragweed or housedust-induced histamine release from basophils of allergic human donors ( IC 50 = 8.6 μ M ). The antiallergy agents proxicromil ( IC 50 = 80 μ M ) and cromolyn (100 μM) were less potent than CI-922 or inactive, respectively. In fragmented lung from actively sensitized guinea pigs, CI-922 ( IC 50 = 1.5 μ M ), blocked the antigen-induced production of LT and was a more potent inhibitor of histamine release ( IC 50 = 13.4 μ M ) than proxicromil ( IC 50 = 72.9 μ M ), or cromolyn (inactive at 1 mM). CI-922 ( IC 50 = 0.9 μ M ) completely inhibited repeated contractions of guinea pig lung strips that were induced by low antigen concentration in the presence of antihistamine (H 1). Nordihydroguaiaretic acid (NDGA) ( IC 50 = 2.8 μ M ), proxicromil ( IC 50 = 6.2 μ M ) and the LT antagonist FPL-55712 ( IC 50 = 3.3 μ M ) also were fully effective, but cromolyn (300 μM) was inactive. In other experiments, CI-922 ( IC 50 = 7.0 μ M ) inhibited a strong, nonrepeatable lung contraction induced with high antigen concentration (histamine responses blocked), and was six times more potent than FPL-55712. Other investigations in isolated tissue preparations showed CI-922 to be a weak inhibitor of LT or histamine-induced effects with no anticholinergic activity. These data show that CI-922 at achievable pharmacologic concentrations ( IC 50 < 15μM) is a potent inhibitor of allergic histamine and LT secretion in several in vitro experimental models, with a spectrum of activity clearly distinct from cromolyn.