A novel series of pyrido[1,2-e]purin-4(3H)-one derivatives containing polar substituents on 5-position were designed and prepared as potential PDE5 inhibitors. This paper reports the synthetic routes, 1H-NMR data, and the PDE5 inhibitory activities of the target compounds. The polar piperazinyl group contained (on 5-position) compound, 3B2, showed the highest activity among the tested derivatives but less potency than sildenafil 1.