A comparison of the inhibitory activity of PDE4 inhibitors on leukocyte PDE4 activity in vitro and eosinophil trafficking in vivo.
1. Phosphodiesterase (PDE) 4 inhibitors have been shown to inhibit eosinophil PDE4 activity in vitro and accumulation of eosinophils in experimental airways inflammation. However, direct effects on eosinophil trafficking have not been studied in detail and it is not known if activity in vitro translates into efficacy in vivo. In the present study, we compared the activity of five PDE4 inhibitors in vitro and against trafficking of (111)In-eosinophils in cutaneous inflammation in the guinea-pig. 2. The rank order of potency for inhibition of PDE4 activity in guinea-pig eosinophil, neutrophil and macrophage, and human neutrophil lysates was RP73401 > SB207499 >CDP840 > rolipram > LAS31025. On TNFalpha production by human PBMC, all inhibitors with the exception of rolipram showed potency similar to their effect on neutrophil lysates. 3. In a brain cerebellum binding assay, the rank order of potency at displacing [3H]-rolipram was RP73401 > rolipram > SB207499 > CDP840 > LAS30125. 4. Trafficking of (111)In-eosinophils to skin sites injected with PAF, ZAP or antigen in sensitized sites was inhibited by oral administration of all PDE4 inhibitors. The rank order of potency was RP73401 = rolipram > LAS31025 > SB207499 > CDP840. 5. With the exception was RP73401, which was the most potent compound in all assays, there was no clear relationship between activity of PDE4 inhibitors in vitro and capacity to inhibit eosinophil trafficking in vivo. Thus, we conclude that in vitro activity of PDE4 inhibitors does not predict in vivo efficacy in an experimental model of eosinophil trafficking.
Cooper
N
N
Chiroscience Limited, Cambridge Science Park.
Teixeira
M M
MM
Warneck
J
J
Miotla
J M
JM
Wills
R E
RE
Macari
D M
DM
Gristwood
R W
RW
Hellewell
P G
PG
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000097:blood; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003872:Dermatitis / Q000097:blood / Q000276:immunology; D004804:Eosinophils / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008264:Macrophages / Q000201:enzymology; D008297:Male; D009504:Neutrophils / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000378:metabolism / Q000494:pharmacology; D020889:Rolipram; D012867:Skin / Q000276:immunology / Q000473:pathology
D001549:Benzamides; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011760:Pyrrolidinones; C102660:CDP 840; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; C087566:piclamilast