Design, synthesis, and biological evaluation of 2-(phenoxyaryl)-3-urea derivatives as novel P2Y1 receptor antagonists

被引：13

作者：

Peng, Jingjing ^{[1
,2
]}

Zhao, Lifen ^{[1
]}

Wang, Lanlan ^{[3
]}

Chen, Hui ^{[1
,2
]}

Qiu, Yunguang ^{[1
,2
]}

Wang, Jiang ^{[1
,2
]}

Yang, Huaiyu ^{[4
]}

Liu, Jun ^{[3
]}

Liu, Hong ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China

[2] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

[3] China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, Nanjing 210009, Jiangsu, Peoples R China

[4] East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 158卷

基金：

中国国家自然科学基金;

关键词：

P2Y(1) receptor antagonist; 2-(phenoxyaryl)-3-urea derivatives; Anti-Platelet; PLATELET-AGGREGATION; ANTIPLATELET AGENTS; HIGH-AFFINITY; DIARYL UREAS; THROMBOSIS; DISCOVERY; POTENT; MICE; PHARMACOKINETICS; CLOPIDOGREL;

D O I：

10.1016/j.ejmech.2018.09.014

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of 2-(phenoxyaryl)-3-urea derivatives were designed, synthesized, and biologically evaluated for their anti-thrombotic activity. Most of compounds exhibited good inhibition against P2Y(1) receptor. Among them, three compounds 11, 12, and 13 demonstrated good P2Y(1) receptor antagonistic potency in vitro (IC50 = 0.62 mu M, 0.82 mu M, and 0.21 mu M, respectively). In antiplatelet aggregation study, four compounds 2, 3, 9, and 13 showed good antiplatelet activity. The possible binding modes of compounds with P2Y(1) receptor were also explored by molecular docking simulation. The docking studies demonstrated that compound 13 interacted well with Phe119 through hydrophobic interaction and modestly improved the P2Y(1) receptor antagonistic activity, making it justifiable for further investigation. (C) 2018 Published by Elsevier Masson SAS.

引用

页码：302 / 310

页数：9

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