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

Jingjing Peng; Lifen Zhao; Lanlan Wang; Hui Chen; Yunguang Qiu; Jiang Wang; Huaiyu Yang; Jun Liu; Hong Liu

doi:10.1016/j.ejmech.2018.09.014

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

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

Authors

Jingjing Peng¹, Lifen Zhao², Lanlan Wang³, Hui Chen¹, Yunguang Qiu¹, Jiang Wang¹, Huaiyu Yang⁴, Jun Liu⁵, Hong Liu⁶

Affiliations

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.

PMID: 30223118
DOI: 10.1016/j.ejmech.2018.09.014

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.

MeSH terms

Animals
Drug Design*
Humans
Male
Molecular Docking Simulation
Platelet Aggregation / drug effects
Platelet Aggregation Inhibitors / chemical synthesis
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacology
Purinergic P2Y Receptor Antagonists / chemical synthesis
Purinergic P2Y Receptor Antagonists / chemistry*
Purinergic P2Y Receptor Antagonists / pharmacology*
Rats, Sprague-Dawley
Receptors, Purinergic P2Y1 / metabolism*
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / pharmacology*

Substances

Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Receptors, Purinergic P2Y1
Urea