Anti-TNF-alpha properties of new 9-benzyladenine derivatives with selective phosphodiesterase-4- inhibiting properties.
In inflammatory cells, intracellular cAMP concentration is regulated by cyclic nucleotide phosphodiesterases 4. Therefore, PDE4 inhibition appears as a rational goal for treating acute or chronic inflammatory diseases. Selective PDE4 inhibitors have been developed, but due to unwanted side effects, search for new selective PDE4-inhibitors had to be pursued. Recently, Boichot et al. (J. Pharmacol. Exp. Ther. (2000) 292, 647-653) showed that 9-benzyladenine derivatives are selective PDE4 inhibitors. In vivo data in animals suggested that they may induce fewer side effects (emesis). We examined the effects of new 9-benzyladenines on TNF-alpha, interleukin (IL)-1beta, IL-6 and IL-8 production by lipopolysaccharide-activated peripheral blood mononuclear cells, and compared them to other PDEs inhibitors. Selected potent 9-benzyladenines, strongly inhibited TNF-alpha production. Interleukin-1beta, IL-6, and IL-8 production was not significantly affected. Our results suggest that some of these new adenines (i.e., NCS 675 and NCS 700), may be potential therapeutic candidates for the treatment of inflammatory diseases.
Reimund
J M
JM
Laboratoire de Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires (UMR 7034 du CNRS), Université Louis Pasteur de Strasbourg, UFR de Sciences Pharmaceutiques, 74 route du Rhin, 67401 Illkirch Cedex, France.
Raboisson
P
P
Pinna
G
G
Lugnier
C
C
Bourguignon
J J
JJ
Muller
C D
CD
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000225:Adenine / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000494:pharmacology
D001549:Benzamides; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; C043898:denbufylline; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000225:Adenine; D010431:Pentoxifylline; C087566:piclamilast