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

Abstract

AbstractGrowing 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 5 i exhibited most potent PDE2A inhibition with IC50 values about 0.049 μM. This compound also showed good selectivity over other PDEs. Docking simulation was performed to insert compound 5 i into the crystal structure of PDE2A at the active site to determine the binding mode. More importantly, compound 5 i exhibited excellent reversal of MPTP‐induced PD model and low acute toxicity in vivo. Based on these results, compound 5 i was evaluated as a promising candidate for the treatment of Parkinson's disease.