Arzneimittelforschung 2010; 60(9): 564-570
DOI: 10.1055/s-0031-1296326
Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs
Editio Cantor Verlag Aulendorf (Germany)

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

Naomasa Asaka
1   Advanced Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama, Japan
Hiroyuki Kakuo
2   Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
Kouichi Ohmori
1   Advanced Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama, Japan
Eiji Sasaki
1   Advanced Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama, Japan
Michinori Togawa
1   Advanced Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama, Japan
Shozo Yamada
1   Advanced Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama, Japan
Tatsuzo Oka
3   Department of Veterinary Pathobiology, Faculty of Agriculture, Kagoshima University, Kagoshima, Japan
Mamoru Kiniwa
1   Advanced Research Laboratory, Taiho Pharmaceutical Co. Ltd., Saitama, Japan
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03. Dezember 2011 (online)


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.

  • References

  • 1 Chung KF. Phosphodiesterase inhibitors in airway disease. Eur J Pharmacol. 2006; 533: 110-7
  • 2 Schudt C, Gantner F, Tenors H, Hatzelmann A. Therapeutic potential of selective PDE inhibitors in asthma. Pulm Pharmacol Ther. 1999; 12: 123-9
  • 3 Essayan DM. Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem Pharmacol. 1999; 57: 965-73
  • 4 Teixeira MM, Gristwood RW, Cooper N, Hellewell PG. Phosphodiesterase (PDE)4 inhibitors: anti-inflammatory drugs of the future?. Trends Pharmacol Sci. 1997; 18: 164-71
  • 5 Giembycz MA. An update and appraisal of the cilomilast phase III clinical development programme for chronic obstructive pulmonary disease. Br J Clin Pharmacol. 2006; 62: 138-52
  • 6 Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet. 2005; 365: 167-75
  • 7 Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomized clinical trials. Lamcet. 2009; 9691: 685-94
  • 8 Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ et al Roflumilast in moderate-to severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomized clinical trials. Lamcet. 2009; 9691: 695-703
  • 9 Huang Z, Ducharme Y, Macdonald D, Robichaud A. The next generation of PDE4 inhibitors. Curr Opin Chem Biol. 2001; 5: 432-8
  • 10 Houslay MD, Schafer P, Zhang KY. Phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005; 10: 1503-19
  • 11 Hebenstreit GF, Feilerer K, Fichte K, Fischer G, Geyer N, Meya U et al Rolipram in major depressive disorder: results of a double-blind comparative study with Imipramine. Pharmacopsychiatry. 1989; 22: 156-60
  • 12 Christensen SB, Guider A, Forster CJ, Gleason JG, Bender PE, Karpinski JM et al 1,4-Cyclohexanecarboxylates: potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma. J Med Chem. 1998; 41: 821-35
  • 13 Thompson WJ, Terasaki WL, Epstein PM, Strada SJ. Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. Adv Cyclic NecleotideRes. 1979; 10: 69-92
  • 14 Torphy TJ, Zhou HL, Cieslinski LB. Stimulation of beta adrenoceptors in a human monocyte cell line (U937) up-regulates cyclic AMP-specific phosphodiesterase activity. J Pharmacol Exp Ther. 1992; 263: 1195-205
  • 15 Bamette MS, Manning CD, Cieslinski LB, Burman M, Christensen SB, Torphy TJ. The ability of phosphodiesterase IV inhibitors to suppress superoxide production in guinea pig eosinophils is correlated with inhibition of phosphodiesterase IV catalytic activity. J Pharmacol Exp Ther. 1995; 273: 674-9
  • 16 Sabroe I, Conroy DM, Gerard NP, Li Y, Collins PD, Post TW et al Cloning and characterization of the guinea pig eosinophil eotaxin receptor, C-C chemokine receptor 3:blockade using amonoclonal antibody in vivo. J Immunol. 1998; 161: 6139-47
  • 17 Flø RW, Naess A, Lund-Johansen F, Maehle BO, Sjursen H, Lehmann V et al Negative selection of human monocytes using magnetic particles covered by anti-lymphocyte antibodies. J Immunol Methods. 1991; 137: 89-94
  • 18 Spina D. PDE4 inhibitors: current status. Br J Pharmacol. 2008; 155: 308-15
  • 19 Torphy TJ, Bamette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD et al Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther. 1999; 12: 131-5
  • 20 Alves AC, Pires AL, Cruz HN, Serra MF, Diaz BL, Cordeiro RS et al Selective inhibition of phosphodiesterase type IV suppresses the chemotactic responsiveness of rat eosinophils in vitro. Eur J Pharmacol. 1996; 312: 89-96
  • 21 Aoki M, Kobayashi M, Ishikawa J, Saita Y, Terai Y, Takaya-ma K et al A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyri-midin-2(1H)-one), with little emetogenic activity. J Pharmacol Exp Ther. 2000; 295: 255-60
  • 22 Davis TG, Peterson JJ, Kou JP, Capper-Spudich EA, Ball D, Nials AT et al The identification of a novel phosphodiesterase 4 inhibitor, l-ethyl-5-{5-[(4-methyl-l-piperazinyl)-methyl]-l,3,4-oxadiazol-2-yl}-N-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[3,4-b]pyridin-4-amine (EPPA-1), with improved therapeutic index using pica feeding in rats as a measure of emetogenicity. J Pharmacol Exp Ther. 2009; 330: 922-31
  • 23 Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther. 2001; 297: 280-90
  • 24 Jin SL, Lan L, Zoudilova M, Conti M. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J Immunol. 2005; 175: 1523-31
  • 25 Robichaud A, Stamatiou PB, Jin SL, Lachance N, MacDo-nald D, Laliberte F et al Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest. 2002; 110: 1045-52
  • 26 Billah MM, Cooper N, Minnicozzi M, Warneck J, Wang P, Hey JA et al Pharmacology of N-(3,5-dichloro-l-oxido-4-pyridinyl) -8-methoxy-2- (trifluoromethyl) -5-quinoline car-boxamide (SCH 351591), a novel, orally active phosphodiesterase 4 inhibitor. J Pharmacol Exp Ther. 2002; 302: 127-37
  • 27 Gale DD, Hofer P, Spina D, Seeds EA, Banner KH, Harrison S et al Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, VI1294. Pulm Pharmacol Ther. 2003; 16: 97-104