title: Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma.
abstract: An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Itadani
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yashiro
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Aratani
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sekiguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Hideki
authors.initials: H
authors.lastname: Moriguchi
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Ohta
authors.forename: Shinya
authors.initials: S
authors.lastname: Takahashi
authors.forename: Akiharu
authors.initials: A
authors.lastname: Ishida
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tajima
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hisaichi
authors.forename: Masaki
authors.initials: M
authors.lastname: Ima
authors.forename: Junya
authors.initials: J
authors.lastname: Ueda
authors.forename: Hiromu
authors.initials: H
authors.lastname: Egashira
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sekioka
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kadode
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yonetomi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakao
authors.forename: Atsuto
authors.initials: A
authors.lastname: Inoue
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nomura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitamine
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujita
authors.affiliation: ∥Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge, Hirakata, Osaka 573-0101, Japan.|⊥Department of Pharmacology, Kyoto Pharmaceutical University, 5 Nakauchi Misasagi, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nabe
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsumura
authors.forename: Akira
authors.initials: A
authors.lastname: Imagawa
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Jun
authors.initials: J
authors.lastname: Takeuchi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ohmoto
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001682:Biological Availability; D002087:Butyrates / Q000494:pharmacology* / Q000627:therapeutic use*; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D020024:Leukotriene Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D018077:Receptors, Leukotriene / Q000187:drug effects*
chemical_list: D002087:Butyrates; D007211:Indoles; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; C000603360:gemilukast; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor