The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4

B. Hughes, D. Howat, H. Lisle, M. Holbrook, T. James, N. Gozzard, K. Blease, P. Hughes, R. Kingaby, G. Warrellow, R. Alexander, J. Head, E. Boyd, M. Eaton, M. Perry, M. Wales, B. Smith, R. Owens, C. Catterall, S. LumbA. Russell, R. Allen, M. Merriman, D. Bloxham, G. Higgs*

*Corresponding author for this work

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Abstract

1 The novel tri-aryl ethane CDP840, is a potent and selective inhibitor of cyclic AMP phosphodiesterase type 4 (PDE 4) extracted from tissues or recombinant PDE 4 isoforms expressed in yeast (IC50s: 4–45 nM). CDP840 is stereo-selective since its S enantiomer (CT 1731) is 10–50 times less active against all forms of PDE 4 tested while both enantiomers are inactive (IC50s: > 100 μm) against PDE types 1, 2, 3 and 5. 2 Oral administration of CDP840 caused a dose-dependent reduction of interleukin-5 (IL-5)-induced pleural eosinophilia in rats (ED50 = 0.03 mg kg−1). The eosinophils in pleural exudates from CDP840-treated animals contained higher levels of eosinophil peroxidase (EPO) than cells from control animals, suggesting a stabilizing effect on eosinophil degranulation. CDP840 was approximately equi-active with the steroid dexamethasone in this model and was 10–100 times more potent than the known PDE 4-selective inhibitors rolipram and RP73401. The activity of CDP840 was not influenced by adrenalectomy, β-sympathomimetics or β-sympatholytics. 3 Antigen-induced pulmonary eosinophilia in sensitized guinea-pigs was reduced dose-dependently by CDP840 (0.01-1 mg kg−1, i.p.) and intracellular EPO levels were significantly higher. CDP840 was more potent in these activities than CT1731 or rolipram and comparable in potency to RP73401. 4 Rolipram or CDP840 were less active than dexamethasone in preventing neutrophil accumulation, or exudate formation in carrageenan-induced pleurisy in rats and thus do not exhibit general antiinflammatory activity. 5 In sensitized guinea-pigs, aerosols of the antigen ovalbumin caused a dose-dependent bronchoconstriction demonstrated by an increase in pulmonary inflation pressure. Administration of CDP840 (0.001-1.0 mg kg−1, i.p.), 1 h before antigen challenge, resulted in dose-dependent reduction in response to antigen. This activity was not due to bronchodilatation since higher doses of CDP840 (3 mg kg−1) did not significantly change the bronchoconstrictor response to histamine. Rolipram was approximately 10 times less active than CDP840 in preventing antigen-induced bronchoconstriction. 6 These results confirm the observations that selective PDE 4 inhibitors reduce antigen-induced bronchoconstriction and pulmonary eosinophilic inflammation. CDP840 is more potent than rolipram in inhibiting native or recombinant PDE 4. Unlike the recently described potent PDE 4 inhibitor RP73401, CDP840 is more active than rolipram in the rat IL-5 model following oral administration. The novel series of tri-aryl ethanes, of which CDP840 is the lead compound, could be the basis of an orally active prophylactic treatment for human asthma.
Original languageEnglish
Pages (from-to)1183-1191
Number of pages9
JournalBritish Journal of Pharmacology
Volume118
Issue number5
DOIs
Publication statusPublished - 01 Jul 1996
Externally publishedYes

Keywords

  • Allergic airway disease
  • Anti-asthmatic
  • Anti-inflammatory
  • Bronchoconstriction
  • CDP840
  • Eosinophilia
  • Esoinophil stabilization
  • Phosphodiesterase inhibitor
  • Rolipram
  • RP73401
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Benzamides/chemistry
  • Humans
  • Interleukin-5/pharmacology
  • Male
  • Phosphoric Diester Hydrolases/genetics
  • Dose-Response Relationship, Drug
  • Neutrophils/drug effects
  • Pyrrolidinones/chemistry
  • Pyridines/chemistry
  • Lung/drug effects
  • Disease Models, Animal
  • Rabbits
  • Airway Resistance/drug effects
  • Guinea Pigs
  • Rats
  • Asthma/drug therapy
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Animals
  • Phosphodiesterase Inhibitors/chemistry
  • Analysis of Variance
  • Eosinophilia/chemically induced
  • Isoenzymes/genetics
  • Bronchoconstriction/drug effects

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