SELECTIVE INHIBITORS OF CYCLE AMT-SPECIFIC PHOSPHODIESTERASE - HETEROCYCLE-CONDENSED PURINES

To reverse the adverse reactions of alkylxanthines and to develop nove l inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), a seri es of heterocycle-condensed purines were designed and synthesized. Som e of these new compounds had similar or more potent and selective inhi bitory activity against PDE IV than known PDE IV inhibitors. The trach eal-relaxant activity of these compounds was closely correlated with t heir PDE IV-inhibitory activity. Moreover, these purine analogues did not have any positive-chronotropic action or adenosine-antagonistic ac tion on isolated heart preparations, which are the particular adverse reactions of alkylxanthines. Among them, yl-4,5,7,8-tetrahydro-3H-imid azo[1,2-i]purin-5-one (1c), which was the most selective and potent PD E TV inhibitor, did not cause emesis in Suncus murinus at a dosage ran ge of 10-100 mg/kg (po), while an imidazole analogue of 1c (4c) and kn own PDE IV inhibitors such as rolipram and denbufylline caused emesis even at 10 or 30 mg/kg.