al-3264 and Hypersensitivity

Antiallergic effects of AL-3264 (N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3-(6-methyl-3- pyridyl)acrylamide, CAS 118420-47-6) were compared with those of ketotifen, oxatomide, azelastine and tranilast in experimental animals. AL-3264 inhibited passive cutaneous anaphylaxis (PCA) in rats with an ED50 value of 6.1 mg/kg p.o. In inhibiting PCA, AL-3264 was the most potent among the antiallergic drugs examined. The anti-PCA effect of AL-3264 was long-lasting. Tolerance was not produced by repeated administration of AL-3264. AL-3264 inhibited antigen-induced bronchoconstriction in actively sensitized rats and in passively sensitized guinea pigs, with ED50 values of 14.5 and 0.44 mg/kg p.o., respectively. In the in vitro experiments, AL-3264 inhibited 5-lipoxygenase activity of guinea pig leukocytes with an IC50 value of 4.9 mumol/l, being the most potent among antiallergic drugs examined, and suppressed the antigen-induced histamine release from rat peritoneal mast cells with an IC50 value of 12.2 mumol/l. AL-3264 antagonized histamine-induced contractions in isolated guinea pig trachea with an IC50 value of 0.16 mumol/l. These results suggest that AL-3264 is an orally active, potent and long-lasting antiallergic compound which inhibits 5-lipoxygenase activity, histamine release and histamine H1 receptors at the similar concentrations.

Topics: Acrylamides; Animals; Antigens; Bronchoconstriction; Guinea Pigs; Histamine Antagonists; Histamine Release; Hypersensitivity; Leukocytes; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Passive Cutaneous Anaphylaxis; Piperazines; Rats; Rats, Wistar; Trachea

A new series of 3-(3-pyridyl)acrylamides 16, 17, 19, and 26, and 5-(3-pyridyl)-2,4-pentadienamides 20-25 were prepared and evaluated for their antiallergic activity. Several of these compounds exhibited more potent inhibitory activities than the parent compound 1a [(E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (3-pyridyl)acrylamide] against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase. Particularly, (E)-N-[4-[4-(diphenylmethyl)-1-piperazinyl]butyl]-3- (6-methyl-3-pyridyl)acrylamide (17p) showed an ED50 value of 3.3 mg/kg po in the rat PCA test, which was one-fifth of ketotifen and oxatomide. As compared with ketotifen and oxatomide, compound 17p (AL-3264) possessed a better balance of antiallergic properties due to inhibition of chemical mediator release, inhibition of 5-lipoxygenase, and antagonism of histamine.

Topics: Acrylamides; Animals; Chemical Phenomena; Chemistry; Guinea Pigs; Histamine Antagonists; Histamine Release; Humans; Hypersensitivity; In Vitro Techniques; Ketotifen; Lipoxygenase Inhibitors; Male; Passive Cutaneous Anaphylaxis; Piperazines; Rats; Rats, Inbred Strains; Structure-Activity Relationship