Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
J Med Chem. 2024 Apr 11;67(7):5502-5537. doi: 10.1021/acs.jmedchem.3c02099. Epub 2024 Mar 29.
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.
患有动脉栓塞性疾病的患者从抗血小板治疗中获益良多。然而，抗血小板药物的出血风险不容忽视。在此，我们描述了发现 2,3-二氢[1,4]二恶烷并[2,3-]苯并呋喃类化合物作为新型 PAR4 拮抗剂。值得注意的是，具有 2,3-二氢-1,4-二恶烷环上的苯氧基亚甲基取代的异构体 和 表现出很强的抗血小板活性（对 为 26.13 nM，对 为 14.26 nM），并在人肝微粒体中显著改善代谢稳定性（对 为 97.6 min，对 BMS-986120 为 11.1 min）。 也表现出良好的口服 PK 特征（小鼠： 为 7.32 h， 为 45.11%）。它们在 6 和 12 mg/kg 的浓度下均表现出整体强效的抗血小板活性，对凝血系统没有影响，出血风险低。我们的工作将促进新型 PAR4 拮抗剂的开发，为动脉栓塞提供更安全的治疗选择。
