Effects of the new benzimidazole derivative TAS-203, an orally active phosphodiesterase 4 inhibitor, on airway inflammation in rats and emetic responses in ferrets

Arzneimittelforschung. 2010;60(9):564-70. doi: 10.1055/s-0031-1296326.


TAS-203 (2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-5-(1H-1,2,4-triazol-1-yl)-1H-benzimidazole, CAS 223909-92-0) is a novel phosphodiesterase 4 (PDE4) inhibitor that has been found to have good anti-inflammatory effects and low emetogenic activity in vivo. In the present studies, the anti-inflammatory profile of TAS-203 was examined and compared with that of cilomilast (CAS 153259-65-5), the most advanced PDE4 inhibitor. TAS-203 inhibited the activity of purified human PDE4 with an IC50 value of 88 nM and also the recombinant PDE4 subtypes (4A, 4B, 4C and 4D) with respective IC50 values of 47, 35, 227 and 43 nM. In the experiments using inflammatory cells, TAS-203 concentration-dependently inhibited platelet-activating factor-induced eosinophil chemotaxis and lipopolysaccharide (LPS)-stimulated tumor necrosis factor-a release from human monocytes with respective IC50 values of 250 and 38.5 nM. For airway inflammation, TAS-203 at 10 mg/kg and cilomilast at 30 mg/kg significantly inhibited antigen-induced airway eosinophilia and LPS-induced airway neutrophilia in rats. The emetogenicity of TAS-203 and cilomilast was evaluated in a ferret model of emesis. The maximum dose of TAS-203 not carrying emesis was 100 mg/kg, while that of cilomilast was less than 10 mg/kg. Finally, TAS-203 was found to be poorly distributed to the brain after oral administration of 10 mg/kg TAS-203 in rats. These results indicate that TAS-203 is an orally active PDE4 inhibitor with potent anti-inflammatory activities and low emetogenicity that may be useful in the treatment of airway inflammatory conditions such as asthma and chronic obstructive pulmonary disease.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents*
  • Benzimidazoles / pharmacokinetics
  • Benzimidazoles / pharmacology*
  • Chemotaxis, Leukocyte / drug effects
  • Cloning, Molecular
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / biosynthesis
  • Cyclohexanecarboxylic Acids / pharmacology
  • Ferrets*
  • Guinea Pigs
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / pathology
  • Lipopolysaccharides / pharmacology
  • Male
  • Nitriles / pharmacology
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Platelet Activating Factor / pharmacology
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred Lew
  • Respiratory Tract Diseases / drug therapy*
  • Respiratory Tract Diseases / pathology
  • Tissue Distribution
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Vomiting / prevention & control*


  • Anti-Inflammatory Agents
  • Benzimidazoles
  • Cyclohexanecarboxylic Acids
  • Lipopolysaccharides
  • Nitriles
  • Phosphodiesterase 4 Inhibitors
  • Platelet Activating Factor
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • TAS-203
  • Cilomilast
  • Cyclic Nucleotide Phosphodiesterases, Type 4