Discovery of 2,3-Dihydro[1,4]dioxino[2,3-]benzofuran Derivatives as Protease Activated Receptor 4 (PAR4) Antagonists with Potent Antiplatelet Aggregation Activity and Low Bleeding Tendency.

Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers and with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent antiplatelet activity (IC = 26.13 nM for and 14.26 nM for ) and significantly improved metabolic stability in human liver microsomes ( = 97.6 min for and 11.1 min for BMS-986120). also displayed good oral PK profiles (mice: = 7.32 h and = 45.11%). Both of them showed overall potent antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.