title: A novel dual antagonist of thromboxane A2 and leukotriene D4 receptors: synthesis and structure-activity relationships of chloroquinolylvinyl derivatives.
abstract: To discover an orally active thromboxane A(2) (TXA(2)) and leukotriene D(4) (LTD(4)) dual antagonist, we designed and synthesized chloroquinolylvinyl derivatives based on the structures of the TXA(2) antagonist daltroban and the LTD(4) antagonist montelukast. Among these derivatives, 4-{[(2-(4-chlorophenylsulfonylamino)-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic acid (18d) showed potent inhibitory activity against U46619-induced aggregation of guinea pig platelets and LTD(4)-induced contraction in the guinea pig ileum, with IC(50) values of 340 nm and 0.40 nm, respectively. Oral administration of 18 d also inhibited both the LTD(4)-induced acceleration of plasma leakage to skin in guinea pig and the U46619-induced increase in airway resistance in guinea pig with ED(50) values of 0.47 mg/kg and 3.3 mg/kg, respectively.
authors.affiliation: Chemistry Research Laboratories, Astellas Pharmaceutical Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. yoshinori.okamoto@jp.astellas.com
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Yokota
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kawazoe
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kubota
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagaoka
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Arakida
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002739:Chloroquinolinols / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D012867:Skin / Q000187:drug effects; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002739:Chloroquinolinols; D007202:Indicators and Reagents; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D018077:Receptors, Leukotriene; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014753:Vinyl Compounds; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C083169:leukotriene D4 receptor