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. Epub 2015 Jul 22.


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.

MeSH terms

  • Animals
  • Asthma / drug therapy*
  • Biological Availability
  • Butyrates / pharmacology*
  • Butyrates / therapeutic use*
  • Dogs
  • Guinea Pigs
  • Humans
  • Indoles / pharmacology*
  • Indoles / therapeutic use*
  • Leukotriene Antagonists / pharmacokinetics
  • Leukotriene Antagonists / pharmacology*
  • Leukotriene Antagonists / therapeutic use*
  • Rats
  • Receptors, Leukotriene / drug effects*


  • Butyrates
  • Indoles
  • Leukotriene Antagonists
  • Receptors, Leukotriene
  • gemilukast
  • cysteinyl leukotriene receptor 2
  • leukotriene D4 receptor