CI-922--a novel, potent antiallergic compound--II. Activity in animal models of allergy

Abstract

CI-922 (3,7-dimethoxy-4-phenyl-N-1H-tetrazol-5-yl-4H-furo [3,2-b]indole-2-carboxamide, L-arginine salt) is an effective antiallergic in guinea pig, rat, and canine models. This in vivo activity is attributed to its ability to inhibit inflammatory mediator release following antigen challenge in these species. Antigen-induced anaphylaxis in guinea pigs (collapse), which is mediated predominantly by histamine, was prevented by i.p. drug pretreatment. CI-922 (5 mg/kg, i.v.) reduced i.v. antigen-induced falls in pulmonary compliance in mepyramine-pretreated, anesthetized guinea pigs. By comparison, cromolyn sodium was inactive in both guinea pig models. In rats, CI-922 given immediately before antigen challenge (ID50 of 0.29 mg/kg, i.v.) was effective and twice as potent as cromolyn sodium and twenty times more potent than proxicromil in preventing i.v. antigen-induced pulmonary anaphylaxis. In addition, when the drugs were given 10 min before antigen challenge, only CI-922 caused a dose-related reduction of bronchoconstriction. CI-922 did not show direct antagonist activity when tested against a serotonin-induced bronchospasm, and exhibited only slight activity against a histamine-induced bronchospasm. CI-922 (0.3 mg/kg, i.v.) also reduced the bronchospasm caused by aerosol antigen (ascaris) challenge in spontaneously allergic dogs. In contrast, proxicromil was inactive in this dog model. The drug also inhibited passive cutaneous anaphylaxis in rats (ID50 of 0.2 to 0.3 mg/kg, i.v. and 0.7 to 6.4 mg/kg, p.o.). These data illustrate that CI-922 is active in several species in vivo, and has a spectrum of antiallergic activity significantly different from cromolyn-like drugs.