-The effects of 9-[(4-acetyl-3-hydroxy-2-
n-propylphenoxy)methyl]-3-(1
H-tetrazol-5-yl)-4
H-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 LTC
4-, LTD
4- and LTE
4-induced contractions of the ileum with IC
50 values of 8 nM, 4 nM and 3 nM, respectively. In the trachea, the agent also antagonized LTD
4- and LTE
4-induced contractions with IC
50 values of 10 nM and 20 nM, respectively. However, LTC
4-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 D
2-, prostaglandin F
2α-induced contractions of the trachea and LTE
4-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 LTC
4 and LTD
4 in anesthetized guinea pigs, but did not inhibit histamine-induced bronchoconstriction. Oral administration of AS-35 also antagonized LTD
4- as well as antigen-induced LT-mediated bronchoconstriction. In addition, LTD
4-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.
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