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

Abstract

TAS-203 (2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-5-(lH-l,2,4-triazol-l-y1)-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 emet-ogenic 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-α 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.

Key words

Airway inflammation - Anti-inflammatory agent - CAS 223909-92-0 - Emesis - Phosphodiesterase 4 inhibitor - TAS-203

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