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

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.

Acetylene Group, Friend or Foe in Medicinal Chemistry

“…The cysteinyl leukotriene (CysLT 1 and CysLT 2 ) receptors are expressed on airway smooth muscle and inflammatory cells, and thus antagonizing these receptors is an attractive strategy for treating asthma. , Itadani and co-workers began optimization of the 2-methylindole-1-acetic acid lead compound 47 that exhibited low permeability (Figure ). They postulated poor permeability of 47 is a result of conformational flexibility and acidic property. This prompted them to replace the trans -double bond with a more linear triple bond, leading to 48 with a retention of dual antagonist activity of 47 .…”

Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

“…3b, c). Moreover, the phenylbutyl group in this and other scaffolds tolerates methyl and halogen decorations in the ortho and meta positions, which enables tuning pharmacological properties of the ligand such as solubility and stability, as exemplified by the development of gemilukast 32 .…”

“…We collected 18 O- and N-derivatives of the common 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid scaffold from previous studies 30,32 , assigned charges for the ligands at pH 7.0, and generated 3D ligand structures from their 2D representations, using Monte Carlo optimization and the MMFF-94 force field. We preprocessed each protein structure (CysLT 1 R-pranlukast, PDB ID 6RZ4; CysLT 2 R-11a, PDB ID 6RZ6) by adding missing residues, optimizing side-chain rotamers, and removing water molecules.…”

Recent Development in Palladium-Catalyzed Domino Reactions: Access to Materials and Biologically Important Carbo- and Heterocycles

“…The terminating step consisted in a Michael addition at the 3-position of the indole, furnishing products in 40–89% yields (Scheme ). Compounds bearing the (3-indolyl)­ethyl moiety were challenging synthetic targets due to the diversity of biologically active tryptamine analogues …”