RO-22-3747 - A NEW ANTIALLERGIC AGENT FOR THE TREATMENT OF IMMEDIATE HYPERSENSITIVITY DISEASES

Abstract

Ro 22-3747 was orally active in 2 animal models of immediate hypersensitivity diseases mediated by IgE, i.e., the rat passive cutaneous anaphylaxis test (ID50 [median inhibitory dose] of 0.65 mg/kg) and a model in which anaphylactic bronchospasm was studied in passively sensitized rats (ID50 of 0.022 mg/kg). In the latter model system Ro 22-3747 was also efficacious by the aerosol route (Ro 22-3747 was 23-fold more potent than disodium cromoglycate by this route of administration). Like disodium cromoglycate (cromoglycate), Ro 22-3747 appears to act in these in vivo models by inhibition of allergic mediator release because it was a potent inhibitor of antigen-induced histamine release from passively sensitized rat peritoneal cells in vitro (IC50 [median inhibitory concentration] values of 0.25 and 1.5 .mu.M for Ro 22-3747 and cromoglycate, respectively) and did not exhibit end organ antagonism to histamine, serotonin or slow reacting substance of anaphylaxis [SRS-A]. The mechanism by which Ro 22-3747 inhibits mediator release does not appear to involve inhibition of .DELTA.5-lipoxygenase, phospholipase A2 or thromboxane synthase. Cromoglycate and Ro 22-3747 appear to have some similarities with regard to their mechanism of action, as they both exhibit a time-dependent loss of inhibitory activity when preincubated with peritoneal cells in vitro before antigen challenge. Pretreatment with one prevented the subsequent inhibition of histamine release by the other. Unlike cromoglycate, Ro 22-3747 (10-5-10-3 M) also inhibited he release of histamine (3-59%), SRS-A (12-49%) and thromboxane (0-55%) from antigen-challenged IgG1-mediated guinea pig lung fragments. Ro 22-3747 is being projected for clinical evaluation as an orally active antiallergic.