Effects of ONO-6950, a novel dual cysteinyl leukotriene 1 and 2 receptors antagonist, in a guinea pig model of asthma

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• 作者：Yasuo Yonetomi ; ^{yonetomi@ono.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Tomohiko Sekioka ; Michiaki Kadode ; Tetsuya Kitamine ; Akihiro Kamiya ; Atsuto inoue ; Takafumi Nakao ; Hiroaki Nomura ; Masayuki Murata ; Shintaro Nakao ; Fumio Nambu ; Manabu Fujita ; Shinji Nakade ; Kazuhito Kawabata
• 关键词：Asthma ; CysLTs ; CysLT2 receptor ; CysLT1/LT2 receptor antagonist ; ONO-6950 ; Glutathione
• 刊名：European Journal of Pharmacology
• 出版年：2015
• 出版时间：15 October 2015
• 年：2015
• 卷：765
• 期：Complete
• 页码：242-248
• 全文大小：563 K

文摘

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.