Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Xing, Junhao; Yang, Lingyun; Zhou, Jinpei; Zhang, Huibin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 23/24(2018)
• Page Start: 5987
• Page End: 5999
• Publication Date: 2018-12-15
• Subjects: Factor Xa -- Venous thrombosis -- Arteriovenous shunt -- Bleeding risk -- H9C2 cell; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.09.012
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A series of anthranilamide derivatives were designed and synthesized. Most of the compounds had significant fXa inhibitoy activity. 16g displayed great in vitro and in vivo antithrombotic activity and low bleeding risk. 16g exhibited satisfactory PK profile. 16g was found to improve hypoxia–reoxygenation-induced H9C2 cell viability. 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 P 1 and P 4 groups led to the discovery of compound16g : 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 that16g 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 by16g .