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  • br Venous thromboembolism VTE is a rare but potentially life

    2021-10-20


    Venous thromboembolism (VTE) is a rare but potentially life-threatening complication of total joint arthroplasty (TJA) . With modern chemoprophylaxis, the incidence of VTE after primary total Sildenafil mesylate mg hip (THA) or total knee (TKA) arthroplasty is commonly estimated between 0.5% and 1%, and VTE is now considered a largely preventable complication of TJA , . Much of this improvement is attributable to the adoption of VTE chemoprophylaxis as standard practice, which has been supported by recommendations from both the American College of Chest Physicians and the American Academy of Orthopaedic Surgeons endorsing a wide range of pharmacologic agents , . Two commonly used modalities of VTE prophylaxis, aspirin and factor-Xa inhibitors (rivaroxaban, apixaban), have become increasingly preferred to injectable medications, such as low-molecular-weight heparins, and drugs with burdensome monitoring requirements, such as warfarin. The efficacy of both aspirin and factor-Xa inhibitors has been well described; however, there remains disagreement regarding which drug is preferable for patients at varying levels of VTE risk , , . Additionally, while bleeding and wound complications are known adverse events associated with these drugs, it Sildenafil mesylate mg is not clear which agent has the more favorable risk profile , , , . Given this uncertainty, ours and other institutions have moved to implement risk-stratification tools to aid clinicians in selecting an agent for thromboprophylaxis; however, data are limited regarding which agents have the most optimal efficacy and risk profile , , .
    Introduction Factor Xa (fXa), a trypsin-like serine protease, plays a key role in the blood coagulation cascade. It can form pro-thrombinase complex with fVa, phospholipids, and Ca2+ to produce thrombin by activating prothrombin during blood clotting in intrinsic and extrinsic coagulation pathways.2, 3 fXa is upstream from thrombin in the coagulation cascade. Inhibition of fXa instead of thrombin can be more effective in diminishing the coagulation cascade. Moreover, Inhibition of fXa has lower risk of bleeding due to its ability to reduce the further generation of thrombin without affecting the existing level of thrombin which should be sufficient to ensure primary hemostasis. Therefore, fXa is a particularly promising target for the development of novel anticoagulants and has attracted great interest in the past decades. Currently, four oral, direct and selective fXa inhibitors have been approved by the U.S. Food and Drug Administration (FDA): rivaroxaban,5, 6 apixaban, edoxaban and betrixaban. Compared with traditional anticoagulants, these novel fXa inhibitors exhibited good oral bioavailability, high specificity and minor drug and food interactions.10, 11 However, they still faced with challenging scenarios due to lack of required monitoring and specific reversal agents for significant bleeding. In addition, they have narrow clinical indications and should not be used in patients with severe renal and hepatic impairment,13, 14 patients with mechanical heart valves. Therefore, it is also necessary to further develop novel and safer fXa inhibitors to promote their use in clinic (See Fig. 1). In our previous studies, we have reported a series of anthranilamide and 2, 3-dihydroquinazolin- 4(1H)-one derivatives as fXa inhibitors.16, 17 As a part of our ongoing research program to develop safer and more effective fXa inhibitors, guided by X-ray crystallography and structure-based design strategies, a series of novel anthranilamide fXa inhibitors were designed and synthesized. The following optimization resulted in the discovery of compound 16g, which was identified as a highly potent and selective FXa inhibitor and warrants further evaluation as a potential candidate for the prevention and treatment of thromboembolic diseases. Additionally, myocardial ischemia (MI) is known to induce the formation of thrombosis, and thrombus is also a cause of MI.18, 19, 20 Thus, compounds possessing both anticoagulant and cardioprotective effects in MI are desirable. The most excellent compound 16g was selected to investigate its effect on hypoxia–reoxygenation -induced H9C2 cell viability. MTT results showed that 16g could inhibite hypoxia– reoxygenation-induced H9C2 cell viability loss.