Thromboembolic disorders including deep venous thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, acute coronary syndromes (ACS) remain the leading cause of morbidity and mortality worldwide and anticoagulants were used for the prevention and treatment of thromboembolism diseases. Traditional anticoagulants such as heparin (unfractionated and low-molecular-weight heparins) and vitamin K antagonists (warfarin) have proved to be effective in the prevention and treatment of these thrombotic diseases. But due to the inconvenient administration and unneglectable side effects for heparins and extensive drug and food interactions for VKAs, their wide clinical use was limited. Thus, identifying novel oral anticoagulants with improved efficacy and safety has become increasingly important.

Factor Xa (FXa) plays a key role within the blood coagulation cascade which makes it a research hotspot in the anticoagulation field. With rivaroxaban as the lead compound, Prof. Yushe Yang’s group in SIMM, CAS designed and synthesized a series of novel [6,6,5] tricyclic fused oxazolidinones. After extensive structure-activity relationship and structure-pharmacokineitc relationship studies, we discovered compound 11a (YG-001), which showed excellent in vitro and in vivo antithrobotic activities and high related enzymes selectivity. In addition, YG-001 exhibited better pharmacokinetic profiles both in rats and dogs compared to rivaroxaban. These data suggest compound YG-001 is a highly potent and selective FXa inhibitor and warrants further evaluation as a potential candidate for the prevention and treatment of thromboembolic disease in venous and arterial systems.

This work was finished by Xue Tao and Ding Shi under the direction of Dr. Yang Yushe and has been published on Journal of Medicinal Chemistry.

Paper link: http://pubs.acs.org/doi/pdf/10.1021/jm501045e

Figure 1. The design and structure optimization of tricyclic fused oxazolidinone FXa inhibitors