The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4.
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 microM) 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, 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.
Hughes
B
B
Celltech Therapeutics Limited, Slough, Berkshire.
Howat
D
D
Lisle
H
H
Holbrook
M
M
James
T
T
Gozzard
N
N
Blease
K
K
Hughes
P
P
Kingaby
R
R
Warrellow
G
G
Alexander
R
R
Head
J
J
Boyd
E
E
Eaton
M
M
Perry
M
M
Wales
M
M
Smith
B
B
Owens
R
R
Catterall
C
C
Lumb
S
S
Russell
A
A
Allen
R
R
Merriman
M
M
Bloxham
D
D
Higgs
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000403:Airway Resistance / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000139:chemically induced; D006168:Guinea Pigs; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000276:immunology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D020889:Rolipram
D001549:Benzamides; D015848:Interleukin-5; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011760:Pyrrolidinones; C102660:CDP 840; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C087566:piclamilast