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

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Discovery of 2,3-Dihydro[1,4]dioxino[2,3-g]benzofuran Derivatives as Protease Activated Receptor 4 (PAR4) Antagonists with Potent Antiplatelet Aggregation Activity and Low Bleeding Tendency
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-29 , DOI: 10.1021/acs.jmedchem.3c02099
Panpan Chen _{1,

2} , Cai Chen ₁ , Yizheng Zheng ₃ , Fangjun Chen ₁ , Zhaojun Liu ₃ , Shenhong Ren ₃ , Hangyu Song ₁ , Tongdan Liu ₃ , Zhipeng Lu ₂ , Hongbin Sun _{1,

4} , Yi Kong ₃ , Haoliang Yuan _{1,

4}

Affiliation

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-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC₅₀ = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T_1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T_1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo 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.

中文翻译：

发现 2,3-二氢[1,4]二恶英[2,3-g]苯并呋喃衍生物作为蛋白酶激活受体 4 (PAR4) 拮抗剂，具有有效的抗血小板聚集活性和低出血倾向

动脉栓塞性疾病患者从抗血小板治疗中获益匪浅。然而，抗血小板药物的出血风险也不容忽视。在此，我们描述了 2,3-二氢[1,4]二恶英[2,3- g ]苯并呋喃化合物作为新型 PAR4 拮抗剂的发现。值得注意的是，化学型为苯氧基亚甲基在 2,3-二氢-1,4-二恶英环上取代的异构体36和37表现出有效的体外抗血小板活性（ 36的 IC ₅₀ = 26.13 nM， 37的 IC 50 = 14.26 nM），并且显着改善人肝微粒体的代谢稳定性（BMS-986120 36时T _1/2 = 97.6 分钟，11.1 分钟）。 36还表现出良好的口服 PK 特征（小鼠： T _1/2 = 7.32 h 和F = 45.11%）。两者在浓度为 6 和 12 mg/kg 时均表现出有效的体外抗血小板活性，对凝血系统没有影响且出血倾向低。我们的工作将促进新型 PAR4 拮抗剂的开发，作为动脉栓塞更安全的治疗选择。

更新日期：2024-03-29

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