title: 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 F2 alpha-induced contractions of the trachea and LTB4-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.
authors.affiliation: Product Development Laboratories, Tokyo Tanabe Co., Ltd., Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kasai
authors.forename: T
authors.initials: T
authors.lastname: Kawashima
authors.forename: S
authors.initials: S
authors.lastname: Omura
authors.forename: Y
authors.initials: Y
authors.lastname: Yanagihara
mesh_terms: D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000008:administration & dosage; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects
chemical_list: D002867:Chromones; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D011725:Pyridines; D011744:Pyrimidinones; D013777:Tetrazoles; C073308:AS 35; C006312:FPL 55712