Antiallergic properties of SQ 13,847, an orally effective agent. II. Activity in vitro

SQ 13,847, a pyrazolo[1,5-c]quinazoline with potent oral antiallergic activity in the rat, was compared with its principal oxidative metabolite, SQ 12,903, for ability to block the release of histamine from the rat mast cell in vitro. SQ 12,903, at concentrations in the range of 0.3 to 2 micrometer, produced 50% inhibition of histamine release reactions triggered by dextran, antirat immunoglobulin (Ig) E or polymyxin B, whereas SQ 13,847 concentration of 100 micrometer or greater were required to produce equivalent inhibitory effects. The greater potency of SQ 12,903 relative to that of SQ 13,847, both in vitro and in passive cutaneous anaphylaxis via the intravenous route, together with the structural similarity of SQ 13,847 is prodrug, requiring oxidation to SQ 12,903 for expression of maximum antiallergic activity. SQ 12,903, disodium cromoglycate and doxantrazole displayed similar time-dependent inhibition and cross-tachyphylaxis, suggesting that all three antiallergic agents block mast cell degranulation via a common mechanism.