2. Academic Validation
  3. Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors

Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors

  • Bioorg Med Chem. 2018 Dec 15;26(23-24):5987-5999. doi: 10.1016/j.bmc.2018.09.012.
Junhao Xing 1,  Lingyun Yang 2,  Jinpei Zhou 3,  Huibin Zhang 4
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
  • 4 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: hb_zhang@hotmail.com.
PMID: 30446438 DOI: 10.1016/j.bmc.2018.09.012
Abstract

Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g.

Keywords

Arteriovenous shunt; Bleeding risk; Factor Xa; H9C2 cell; Venous thrombosis.

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