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.