Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors

Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for Alzheimer's disease and type 2 diabetes mellitus. A series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. Four of them exhibited excellent inhibitory activity against PDE9A and low cell toxicity. The most effective compound 11a gave the IC50 of 1.0 nmol/L towards PDE9, which was significantly better than the reference compounds PF-04447943 and BAY 73-6691.275