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 mu M) with a good selectivity toward PDE3 and PDE5. The same compounds demonstrate low affinity for the HARBS site with IC50 values of 12-69 mu M (IC50 for Rolipram = 3.6 nM). Drug Dev Res 72:274-288, 2011. (C) 2010 Wiley-Liss, Inc.