Synthesis and evaluation of anthranilamide-based derivatives as FXa inhibitors

// Changjiang Huang 1, 2 , Wenzhi Wang 3 , Yao Li 2 , Shijun Zhang 2 , Fancui Meng 2 , Weiren Xu 2 , Jing Yuan 2 , Ligong Chen 1, 4, 5 1 School of Chemical Engineering and Technology, Tianjin University, Tianjin, China 2 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, China 3 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, China 4 Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, China 5 Tianjin Engineering Research Center of Functional Fine Chemicals, Tianjin, China Correspondence to: Jing Yuan, email: yuanj@tjipr.com Ligong Chen, email: lgchen@tju.edu.cn Keywords: thrombosis, thromboembolic diseases, anticoagulants, factor Xa inhibitors, thrombin and docking simulation Received: November 23, 2016      Accepted: March 10, 2017      Published: March 21, 2017 ABSTRACT Factor Xa (FXa) plays a significant role in the blood coagulation cascade and is a promising target for anticoagulation drugs. Three oral FXa inhibitors have been approved by FDA for treating thrombotic diseases. In this study, 43 novel compounds were synthesized anthranilamide-based FXa inhibitors aiming to ameliorate the toxicity of traditional FXa inhibitors in clinic. The data indicated that the compounds 6a, 6a-b, 6a-e, 6k, 6k-a and 6k-b showed remarkable FXa inhibitory activity and excellent selectivity over thrombin in vitro . Selected compounds also exhibited anticoagulant activities in vitro consequently and were potent novel anti-coagulators in further.