Peptide Leukotriene Antagonistic Activity of AS-35, a New Antiallergic Drug

Abstract

-The effects of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1, 2-a]pyrimidin-4-one (AS-35), a newly synthesized compound, on leukotrienes (LTs) antagonistic activities were investigated in vitro and in vivo. In isolated guinea pig preparations, AS-35 antagonized LTC₄-, LTD₄- and LTE₄-induced contractions of the ileum with IC₅₀ values of 8 nM, 4 nM and 3 nM, respectively. In the trachea, the agent also antagonized LTD₄- and LTE₄-induced contractions with IC₅₀ values of 10 nM and 20 nM, respectively. However, LTC₄-induced tracheal contraction in the presence of L-serine borate was not antagonized by AS-35. Histamine-, acetylcholine-, serotonin- and bradykinin-induced contractions of the ileum, carbachol-, prostaglandin D₂-, prostaglandin F_2α-induced contractions of the trachea and LTE₄-induced chemotaxis of rat polymorphonuclear leukocytes were not inhibited by AS-35. As to the in vivo models, AS-35 (i.v.) dose-dependently antagonized bronchoconstriction induced by i.v.-injection of LTC₄ and LTD₄ in anesthetized guinea pigs, but did not inhibit histamine-induced bronchoconstriction. Oral administration of AS-35 also antagonized LTD₄- as well as antigen-induced LT-mediated bronchoconstriction. In addition, LTD₄-induced increase in the cutaneous vascular permeability of guinea pig was inhibited by the drug (p.o.). These results indicate that AS-35 is an orally effective, potent and selective peptide LT antagonist.