Discovery of a potent, orally available dual CysLT₁ and CysLT₂ antagonist with dicarboxylic acid

Bioorg Med Chem. 2015 May 1;23(9):2079-97. doi: 10.1016/j.bmc.2015.03.011. Epub 2015 Mar 7.


A potent, orally available dual CysLT₁ and CysLT₂ receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC₅₀: CysLT₁=13nM, CysLT₂=25 nM) showed excellent pharmacokinetic profiles (%Frat=100) compared with our previously reported compound 1 (%Frat=1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%Frat⩾40) in rats (HBDs: ⩽2, ClogP: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification.

Keywords: CysLT(1); CysLT(2); Dicarboxylic acid; Dual antagonist; HBDs; Pharmacokinetics.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • CHO Cells
  • Caco-2 Cells
  • Cricetulus
  • Dicarboxylic Acids / administration & dosage*
  • Dicarboxylic Acids / chemistry
  • Dicarboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Leukotriene Antagonists / administration & dosage*
  • Leukotriene Antagonists / chemistry
  • Leukotriene Antagonists / pharmacology*
  • Molecular Structure
  • Receptors, Leukotriene / metabolism*
  • Structure-Activity Relationship


  • Dicarboxylic Acids
  • Leukotriene Antagonists
  • Receptors, Leukotriene
  • cysteinyl leukotriene receptor 2
  • leukotriene D4 receptor