Anti-TNF-alpha properties of new 9-benzyladenine derivatives with selective phosphodiesterase-4-inhibiting properties

In inflammatory cells, intracellular cAMP concentration is regulated by cyc lic nucleotide phosphodiesterases 4. Therefore, PDE4 inhibition appears as, a rational goal for treating acute or chronic inflammatory diseases. Selec tive PDE4 inhibitors have been developed, but due to unwanted side effects, search for new selective PDE4-inhibitors had to be pursued. Recently, Boi- chot et al. (J. Pharmacol. Exp. Ther. (2000) 292, 647-653) showed that 9-be nzyladenine derivatives are selective PDE4 inhibitors. In vivo data in anim als suggested that they may induce fewer side effects (emesis). We examined the effects of new 9-benzyladenines on TNF-alpha, interleukin (IL)-1 beta, IL-6 and IL-8 production by lipopolysaccharide-activated peripheral blood mononuclear cells, and compared them to other PDEs inhibitors. Selected pot ent 9-benzyladenines, strongly inhibited TNF-alpha production. Interleukin- 1 beta, IL-6, and IL-8 production was not significantly affected. Our resul ts suggest, that some of these new adenines (i.e., NCS 675 and NCS 700), ma y be potential therapeutic candidates for the treatment of inflammatory dis eases. (C) 2001 Academic Press.