Design and Synthesis of PDE2A Inhibitors for the Treatment of Parkinson's Disease

Growing evidence confirms the potential of PDE inhibitors including PDE 1, 2, 4, 7 and 10 inhibitors for the treatment of Parkinson's disease, a public health problem. There is a great need to find a way to prevent and delay the disease. Therefore, a series of novel quinolinone derivatives were synthesized and investigated for their ability to inhibit PDE2A. Most of the synthesized compounds have shown good activity against PDE2A. Among these analogues, compound 5i exhibited most potent PDE2A inhibition with IC50 values about 0.049 mu M. This compound also showed good selectivity over other PDEs. Docking simulation was performed to insert compound 5i into the crystal structure of PDE2A at the active site to determine the binding mode. More importantly, compound 5i exhibited excellent reversal of MPTP-induced PD model and low acute toxicity in vivo. Based on these results, compound 5i was evaluated as a promising candidate for the treatment of Parkinson's disease.