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Eur J Med Chem. 2018 Oct 5;158:302-310. doi: 10.1016/j.ejmech.2018.09.014. Epub 2018 Sep 6.

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

Author information

1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
2
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
3
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.
4
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
5
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: junliu@cpu.edu.cn.
6
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China. Electronic address: hliu@simm.ac.cn.

Abstract

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 P2Y1 receptor. Among them, three compounds 11, 12, and 13 demonstrated good P2Y1 receptor antagonistic potency in vitro (IC50 = 0.62 μM, 0.82 μM, and 0.21 μM, respectively). In antiplatelet aggregation study, four compounds 2, 3, 9, and 13 showed good antiplatelet activity. The possible binding modes of compounds with P2Y1 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 P2Y1 receptor antagonistic activity, making it justifiable for further investigation.

KEYWORDS:

2-(phenoxyaryl)-3-urea derivatives; Anti-Platelet; P2Y(1) receptor antagonist

PMID:
30223118
DOI:
10.1016/j.ejmech.2018.09.014
[Indexed for MEDLINE]

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