Discovery of Highly Potent Dual CysLT₁ and CysLT₂ Antagonist

The benzoxazine derivative, (2<i>S</i>)-4-(3-carboxypropyl)-8-{[4-(4-phenylbutoxy)­benzoyl]­amino}-3,4-dihydro-2<i>H</i>-1,4-benzoxazine-2-carboxylic acid (<b>19</b>, ONO-2050297), was identified as the first potent dual CysLT₁ and CysLT₂ antagonist with IC₅₀ values of 0.017 μM (CysLT₁) and 0.00087 μM (CysLT₂), respectively

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

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

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

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