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

被引：73

作者：

Hughes, B ^{[1
]}

Howat, D ^{[1
]}

Lisle, H ^{[1
]}

Holbrook, M ^{[1
]}

James, T ^{[1
]}

Gozzard, N ^{[1
]}

Blease, K ^{[1
]}

Hughes, P ^{[1
]}

Kingaby, R ^{[1
]}

Warrellow, G ^{[1
]}

Alexander, R ^{[1
]}

Head, J ^{[1
]}

Boyd, E ^{[1
]}

Eaton, M ^{[1
]}

Perry, M ^{[1
]}

Wales, M ^{[1
]}

Smith, B ^{[1
]}

Owens, R ^{[1
]}

Catterall, C ^{[1
]}

Lumb, S ^{[1
]}

Russell, A ^{[1
]}

Allen, R ^{[1
]}

Merriman, M ^{[1
]}

Bloxham, D ^{[1
]}

Higgs, G ^{[1
]}

机构：

[1] CELLTECH THERAPEUT LTD,SLOUGH SL1 4EN,BERKS,ENGLAND

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 1996年 / 118卷 / 05期

关键词：

CDP840; phosphodiesterase inhibitor; allergic airway disease; eosinophilia; anti-inflammatory; bronchoconstriction; anti-asthmatic; eosinophil stabilization; RP73401; rolipram;

D O I：

10.1111/j.1476-5381.1996.tb15522.x

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 (IC(50)s: 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 (IC(50)s: >100 mu M) 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 (ED(50)=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, beta-sympathomimetics or beta-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 anti-inflammatory 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.

引用

页码：1183 / 1191

页数：9

共 36 条

[1] PRIMARY SEQUENCE OF CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE ISOZYMES AND THE DESIGN OF SELECTIVE INHIBITORS [J].