Oxatomide and derivatives as inhibitors of mediator release from a mast cell model. Structure-activity relationships.

A series of benzimidazolone and benzimidazole analogues of the antiallergic drug oxatomide (1-¿3-[4-(diphenylmethyl)-1-piperazinyl]propyl¿-1,3-dihydro-2H- benzimidazol-2-one, CAS 60607-34-3) [formula: see text], was evaluated for inhibiting the release of the performed mediator beta-hexosaminidase from the rat basophilic leukemia (RBL-2H3) cell line. Activation of the cells was induced by antigen, or by the calcium ionophore A23187 (calcimycin) in combination with or without the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). For the active compounds, inhibition of exocytosis was found with all triggers, with the antigen trigger being somewhat more sensitive. This indicates that the compounds influence several steps in the signal transduction route leading to exocytosis. The activity of the compounds is not totally aspecific as small structural changes strongly affect the inhibiting activity. Introduction of a chlorine substituent at the 6-position of the benzimidazolone group results in loss of activity. There does not seem to be a significant activity difference between the benzimidazolone and benzimidazole analogues. Analogues with n < 3, n > 5 or a branched alkyl chain between the piperazinyl and the benzimidazol(on)e moiety lose inhibitory activity. Secretion of the newly formed mediator arachidonic acid and its metabolites was affected by the compounds comparable to the effect on the release of beta-hexosaminidase. The anti-allergic activity did not correlate with the histamine H1-receptor antagonistic activity.