title: Effects of ONO-6950, a novel dual cysteinyl leukotriene 1 and 2 receptors antagonist, in a guinea pig model of asthma.
abstract: We assessed in this study the anti-asthmatic effects of ONO-6950, a novel cysteinyl leukotriene 1 (CysLT1) and 2 (CysLT2) receptors dual antagonist, in normal and S-hexyl glutathione (S-hexyl GSH)-treated guinea pigs, and compared these effects to those of montelukast, a CysLT1 selective receptor antagonist. Treatment with S-hexyl GSH reduced animals LTC4 metabolism, allowing practical evaluation of CysLT2 receptor-mediated airway response. ONO-6950 antagonized intracellular calcium signaling via human and guinea pig CysLT1 and CysLT2 receptors with IC50 values of 1.7 and 25 nM, respectively (human receptors) and 6.3 and 8.2 nM, respectively (guinea pig receptors). In normal guinea pigs, both ONO-6950 (1 or 0.3 mg/kg, p.o.) and the CysLT1 receptor antagonist montelukast (0.3 or 0.1 mg/kg, p.o.) fully attenuated CysLT1-mediated bronchoconstriction and airway vascular hyperpermeability induced by LTD4. On the other hand, in S-hexyl GSH-treated guinea pigs ONO-6950 at 3 mg/kg, p.o. or more almost completely inhibited bronchoconstriction and airway vascular hyperpermeability elicited by LTC4, while montelukast showed only partial or negligible inhibition of these airway responses. In ovalbumin sensitized guinea pigs, treatment with S-hexyl GSH on top of pyrilamine and indomethacin rendered antigen-induced bronchoconstriction sensitive to both CysLT1 and CysLT2 receptor antagonists. ONO-6950 strongly inhibited this asthmatic response to the level attained by combination therapy with montelukast and BayCysLT2RA, a selective CysLT2 receptor antagonist. These results clearly demonstrate that ONO-6950 is an orally active dual CysLT1/LT2 receptor antagonist that may provide a novel therapeutic option for patients with asthma.
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan. Electronic address: yonetomi@ono.co.jp.
authors: Yasuo
authors: Y
authors: Yonetomi
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Tomohiko
authors: T
authors: Sekioka
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Michiaki
authors: M
authors: Kadode
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Tetsuya
authors: T
authors: Kitamine
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Akihiro
authors: A
authors: Kamiya
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Atsuto
authors: A
authors: inoue
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Takafumi
authors: T
authors: Nakao
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Hiroaki
authors: H
authors: Nomura
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Masayuki
authors: M
authors: Murata
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Shintaro
authors: S
authors: Nakao
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Fumio
authors: F
authors: Nambu
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Manabu
authors: M
authors: Fujita
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Shinji
authors: S
authors: Nakade
authors: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima-gun, Osaka 618-8585, Japan.
authors: Kazuhito
authors: K
authors: Kawabata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D002087:Butyrates / Q000008:administration & dosage / Q000627:therapeutic use*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D015394:Molecular Structure; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000098:blood supply / 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; D002118:Calcium
keywords: Asthma; CysLT(1)/LT(2) receptor antagonist; CysLT(2) receptor; CysLTs; Glutathione; ONO-6950