Design,Synthesis And Biological Evaluation Of MAO-B Selective Inhibitors Based On Rasagiline

Parkinson’s disease（PD）,also known as paralysis agitans,is the second largest neurodegenerative disease after Alzheimer’s disease.The symptoms of PD include shaking,rigidity,slowness of movement,and difficulty with walking.PD mostly occurs on the elderly and seriously threats their health.Studies have shown that the occurrence of PD is related to the overexpression of Monoamine oxidase B（MAO-B）,suggesting that MAO-B could be used as a target for the treatment of PD.Currently,a few MAO-B inhibitors,such as Rasagiline,Selegiline,and Safinamide,have been marketed successfully.In addition,many small molecule MAO-B inhibitors currently have been reported.However,there are no clinically curable drugs for PD,and current drugs and inhibitors have disadvantages,such as poor efficacy,low selectivity,and unsatisfactory pharmacokinetics.Therefore,continuing to develop novel MAO-B inhibitors with high selectivity,high potency and ideal pharmacokinetics is need.To find more potent and selective MAO-B inhibitors with novel chemical scaffold,we designed and synthesized a series of new 2,3-dihydro-1H-inden-1-amine derivatives on basis of our previous study.Furthermore,the corresponding structure-activity relationship（SAR）of these compounds is detailedly discussed.Compounds L4(IC₅₀=0.11μM),L8(IC₅₀=0.18μM),L16(IC₅₀=0.27μM)and L17(IC₅₀=0.48μM)showed similar MAO-B inhibitory activity as Selegiline.Moreover,L4,L16 and L17 also exhibited comparable selectivity with Selegiline,indicating that L4,L16 and L17 could be promising selective MAO-B inhibitors for further study.In the last,The structures of the obtained compounds with excellent activity and selectivity lays a good foundation for the subsequent design of MAO-B inhibitor with higher activity and selectivity.