Design, synthesis and biological evaluation of novel 2,3-dihydroquinazolin- 4(1H)-one derivatives as potential fXa inhibitors.
Coagulation factor Xa (fXa) is a particularly attractive target for the development of effective and safe anticoagulants. In this study, novel 2,3-dihydroquinazolin-4(1H)-one derivatives were designed as potential fXa inhibitors based on anthranilamide structure which has been reported in our previous research. The experimental data showed that most of the designed compounds exhibited significant in vitro potency against fXa. Among them, compound 8e displayed the strongest potency against fXa with the IC50value of 21 nM and highly selectivity versus thrombin (IC50= 67 μM) and excellent in vitro antithrombotic activity with its 2 × PT value of 1.2 μM and 2 × aPTT value of 0.6 μM. In addition, 8e also displayed excellent in vivo antithrombotic activity in the rat arteriovenous shunt (AV-SHUNT) model. The bleeding risk evaluation showed that 8e had a similar safety profile as that of betrixaban. All results demonstrated that compound 8e could be considered as a potential fXa inhibitor for the prevention and treatment of thromboembolic diseases.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, 210009 Nanjing, PR China. Electronic address: xingjhcpu@163.com.
Junhao
J
Xing
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, 210009 Nanjing, PR China.
Lingyun
L
Yang
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, 210009 Nanjing, PR China.
Yifei
Y
Yang
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, 210009 Nanjing, PR China.
Leilei
L
Zhao
Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
Qiangqiang
Q
Wei
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, 210009 Nanjing, PR China.
Jian
J
Zhang
Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
Jinpei
J
Zhou
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, 210009 Nanjing, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
Huibin
H
Zhang
D000818:Animals; D015195:Drug Design; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D062105:Molecular Docking Simulation; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control
D065427:Factor Xa Inhibitors; D052999:Quinazolinones; D015951:Factor Xa
Anticoagulant; Arteriovenous shunt; Bleeding risk; Factor Xa; Thromboembolic diseases; fXa inhibitor