Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma

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• 作者：Satoshi Itadani ; Kentaro Yashiro ; Yoshiyuki Aratani ; Tetsuya Sekiguchi ; Atsushi Kinoshita ; Hideki Moriguchi ; Nobukazu Ohta ; Shinya Takahashi ; Akiharu Ishida ; Yohei Tajima ; Katsuya Hisaichi ; Masaki Ima ; Junya Ueda ; Hiromu Egashira ; Tomohiko Sekioka ; Michiaki Kadode ; Yasuo Yonetomi ; Takafumi Nakao ; Atsuto Inoue ; Hiroaki Nomura ; Tetsuya Kitamine ; Manabu Fujita ; Takeshi Nabe ; Yoshiyuki Yamaura ; Naoya Matsumura ; Akira Imagawa ; Yoshisuke Nakayama ; Jun Takeuchi ; Kazuyuki Ohmoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：58
• 期：15
• 页码：6093-6113
• 全文大小：966K
• ISSN：1520-4804

文摘

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.