Antiallergic activity profiles in vitro of RHC 3164 and related compounds. I. A lack of correlation between inhibition of cyclic nucleotide phosphodiesterases and antigen-induced release of histamine from rat mast cells.

A series of 26 compounds belonging to the chemical class of (1,2,4)triazolo(4,3-a)-quinoxaline-1,4-diones have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis. Effects of these and other known antiallergic agents on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells have also been investigated. 18 compounds were potent (I50 less than or equal to 45 microM) inhibitors of antigen-induced release of histamine (AIR) from rat mast cells (RMC), 3 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 25 microM) and none of the compounds significantly affected AIR from guinea pig lung slices. 13 of the compounds were more potent than theophylline as inhibitors of cyclic AMP-PDE and/or cyclic GMP-PDE from RMC. Parallel concentration-response curves for the inhibition of cyclic AMP-PDE and cyclic GMP-PDE indicated that these compounds probably interact with enzyme in the same manner. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC by these compounds revealed no statistically significant correlation between the inhibition of AIR and inhibition of cyclic AMP-PDE or cyclic GMP-PDE. We conclude: (1) some of these compounds are potent inhibitors of immunologic release of histamine from RMC with an in vitro activity profile similar to that of DSCG, and (2) inhibition of cyclic AMP or cyclic GMP hydrolysis by cNUD-PDE by these compounds, DSCG, and 6 known antiallergic agents is not the biochemical mechanism by which they inhibit AIR from RMC.

Antiallergic activity profiles in vitro of RHC 3164 and related compounds. II. Comparison of RHC 3164 with disodium cromoglycate.

RHC 3164 has been investigated for its antiallergic activities in 3 in vitro models of anaphylaxis. RHC 3164 was 6 times more potent than DSCG as an inhibitor of antigen-induced release of histamine (AIR) from rat mast cells (RMC) and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties, cross-tachyphylaxis to DSCG, and inability to inhibit nonimmunologic release of histamine. Neither RHC 3164 nor DSCG had any effect on immunologic release of histamine from human basophils or guinea pig lung slices. We conclude that RHC 3164 is a potent inhibitor of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG.

In vitro and in vivo immunopharmacologic properties of a new antiallergic agent RHC 3414.

The antiallergic activity profile of RHC 3414 (7-phenylpyrido (3', 2': 4, 5)-thieno (3.2-d)-1, 2, 3-triazine-4(3H)-one) has been compared with that of disodium cromoglycate (DSCG) in several in vitro and in vivo models of anaphylaxis and inflammation. RHC 3414 was approximately 50 times more potent than DSCG as an inhibitor of antigen-induced release of histamine (AIR) from rat mast cells (RMC) in vitro. As an inhibitor of mediator release, the activity profile of RHC 3414 was identical to that of DSCG in the following respects: inhibition of IgE-mediated release of histamine from RMC but not human basophils (HUB), rapid loss of inhibitory activity as a function of time prior to antigen challenge, inability to inhibit the release of histamine from RMC stimulated by non-immunologic secretagogues as well as IgG1-mediated histamine release from guinea-pig lung slices. In vivo, given orally the sodium salt of RHC 3414 (RHC 3414-Z) was a potent inhibitor of passive cutaneous anaphylaxis (PCA) in the rat. Administered intraperitoneally, RHC 3414-Z was approximately 30 times as potent as DSCG as an inhibitor of IgE-mediated PCA in the rat without any antihistaminic or antiserotonin activity. RHC 3414-Z also inhibited adjuvant-induced inflammatory responses in the rat but had no effect on carrageenan-induced edema formation in vivo or on phospholipase A2 or cyclooxygenase activity in vitro. We conclude that RHC 3414 is a potent antiallergic agent with a mechanism of action similar to that of DSCG. In addition, RHC 3414 may possess the ability to inhibit chronic inflammatory processes, an attribute which should prove useful in the prophylactic treatment of asthma.

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.

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 (I50 less than or equal to 50 microM) 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 (I50 less than or equal to 100 microM). 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 Ca2+ 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 IgG1 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.

Antiallergic activity profile in vitro of RHC 2963 and related compounds.

RHC 2963 (7-methyl-pyrido (3',2':4,5)-thieno (3,2-d)-1,2,3 triazine-4(3H)-one and 20 related compounds have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis and for their effects on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells (RMC). Nine compounds were potent (I50 less than or equal to 80 microM) inhibitors of antigen-induced release of histamine (AIR) from RMC, 2 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 60 microM) and one compound inhibited AIR from guinea pig lung slices (I50 = 55 microM). RHC 2963 was 18 times more potent than disodium cromoglycate (DSCG) as inhibitor of AIR from RMC and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties and inability to inhibit non-immunologic release of histamine induced by compound 48/80. Neither RHC 2963 nor DSCG had any effect on anti-IgE-induced release of histamine from human basophils or IgG1-mediated release of histamine from guinea pig lung. Twelve of the compounds in this chemical series were more potent than theophylline as inhibitors of cyclic AMP and/or cyclic GMP phosphodiesterase (PDE) from RMC. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC revealed no statistically significant correlation between the inhibition of AIR and inhibition of cAMP- or cGMP-PDE. We conclude: (1) RHC 2963 and some of the related compounds are potent inhibitors of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG, and (2) inhibition of cAMP- or cGMP-PDE by these compounds is not the biochemical mechanism by which they inhibit AIR from RMC.

In vitro and in vivo activity profile of RHC 2851: a new orally effective antiallergic agent.

RHC 2851 has been investigated for its antiallergic activity in three in vitro and two in vivo models of anaphylaxis. We have also compared its activity profile in these models with that of disodium cromoglycate (DSCG), doxantrazole, ketotifen and oxatomide. RHC 2851, given i.p., was 6 times more potent than DSCG, and given orally it was 3 times more potent than doxantrazole. As an inhibitor of mediator release, the activity profile of RHC 2851 was identical to that of DSCG in the following respects: inhibition of IgE-mediated in vitro release of histamine from rat mast cells (RMC) but not human basophils (HuB), possession of tachyphylactic properties and demonstration of rapid loss of inhibitory activity as a function of time before antigen challenge as well as inability to inhibit IgG1-mediated release of histamine, both in vitro and in vivo, and lack of mediator antagonist activity. Ketotifen and oxatomide did not inhibit either IgE or IgG1-mediated release of histamine in vitro or in vivo, and were potent mediator antagonists in vivo. We conclude that RHC 2851 is an orally effective inhibitor of mediator release with a mechanism of action similar to that of DSCG and different from that of ketotifen and oxatomide.

RHC 3024: antiallergic activity in vitro and comparison with disodium cromoglycate and other antiallergic agents.

RHC 3024 has been investigated for its antiallergic activity in three in vitro models of anaphylaxis. We have also compared its activity profile in these models with that of disodium cromoglycate (DSCG) and other antiallergic agents. As an inhibitor of antigen-induced release of histamine from rat mast cells RHC 3024 was 4 times more potent than DSCG. In the same model the activity profile of RHC 3024 was identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, reversibility of the inhibition, tachyphylaxis and cross-tachyphylaxis to each other and inability to inhibit histamine release stimulated by Ca++ ionophore, dextran/phosphatidyl serine and compound 48/80. Both drugs had no effect in the other two models, IgG1-mediated histamine release from guinea pig lung and anti-IgE-induced histamine release from human basophils. We conclude: (1) RHC 3024 is a potent inhibitor of mediator release with a mechanism of action similar to that of DSCG, M&B 22,948, PRD-92-Ea and AH-7725 and (2) the in vitro activity profiles of proxicromil, doxantrazole, ICI 74,917 and WY-16,922 are different from DSCG and RHC 3024.