RHC 3288 [1-methyl-2(1,3,4-oxadiazol-2(3H)-one-5-yl) benzimidazole] and related compounds: Novel inhibitors of histamine release from rat mast cells and human basophils

Abstract

RHC 3288 [1-methyl-2(1,3,4-oxadiazol-2(3H)-one-5-yl) benzimidazole] and twenty-five related 5-substituted oxadiazolones have been investigated for their antiallergic activities in three in vitro models of anaphylaxis. Sixteen compounds were potent (I 50 ⩽ 50 μM) inhibitors of antigen-induced release of histamine (AIR) from rat mast cells (RMC), and seven compounds inhibited anti-IgE-induced release of histamine from human basophils (I 50 ⩽ 100 μM). The antiallergic activity profiles of RHC 3288 and three other compounds in these models have been compared with that of disodium cromoglycate (DSCG). As inhibitors of AIR from RMC, RHC 3288, 3334, 3354 and 3380 were 3 to 10 times more potent than DSCG. In the same model (AIR from RMC), activity profiles of all four RHC compounds were identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylaxis and cross-tachyphylaxis to each other, and inability to inhibit histamine release stimulated by Ca 2+ ionophore, dextran + phosphatidyl serine and compound 48/80. RHC 3288, 3334, 3354 and DSCG had no effect in the other two models, histamine release from guinea pig lung mediated predominantly by IgG 1 class of antibodies and anti-IgE-induced histamine release from human basophils. We conclude that RHC 3288 is a potent inhibitor of mediator release with a mechanism of action similar to that of DSCG.