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

  • J Med Chem. 2015 Aug 13;58(15):6093-113. doi: 10.1021/acs.jmedchem.5b00741.
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  1  2 ,  Yoshiyuki Yamaura ,  Naoya Matsumura ,  Akira Imagawa ,  Yoshisuke Nakayama ,  Jun Takeuchi ,  Kazuyuki Ohmoto
Affiliations
  • 1. ∥Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge, Hirakata, Osaka 573-0101, Japan.
  • 2. ⊥Department of Pharmacology, Kyoto Pharmaceutical University, 5 Nakauchi Misasagi, Yamashina, Kyoto 607-8414, Japan.
PMID: 26200813 DOI: 10.1021/acs.jmedchem.5b00741
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.

Products