Synthesis and evaluation as PDE4 inhibitors of pyrimidine-2,4-dione derivatives

A series of nitraquazone analogs with a pyrimidindione core was synthesized and tested for inhibitory activity on PDE4, selectivity versus PDE3 and PDE5 and for affinity towards the rolipram high-affinity binding site (HARBS). The 5-anilino derivatives 13–18 showed the best profile combining appreciable PDE4 inhibitory activity (IC50 5–14 microM) with a good selectivity toward PDE3 and PDE5. The same compounds demonstrate low affinity for the HARBS site with IC50 values of 12–69 mM (IC50 for Rolipram=53.6 nM).