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  • The results show that pimarane and

    2021-10-21

    The results show that -pimarane and -strobane diterpenoids exert inhibitory effects on FXa suggesting that they may have potential as FXa inhibitor. However, it should be noted that some compounds such as compounds , , , and are poorly bioavailable. Thus, the current study indicates that the number, location, orientation of the H-Bond Donor and Mevastatin acceptor, as well as the skeleton of the ring C, may be essential for the inhibitory effects of the diterpenoids against the invasion of FXa. In conclusion, we developed a simple and efficient method for the synthesis of -norstrobane diterpenoids. The synthesized compounds were evaluated for their antithrombotic potential by measuring the inhibitory effects on FXa. Three compounds , , and showed slightly higher activity. The structure–activity relationship data provide insights for further optimization of the -pimarane and -strobane diterpenoids in discovery of new FXa inhibitors. Acknowledgments This work was financially supported by the National Natural Science Foundation of China – China (Grant No. 81172943), the National Major Scientific and Technological Special Projects for “Significant New Drugs Development” during the Twelfth Five-year Plan Period – China (No. 2012ZX09103201-022), and Shandong Province Science Foundation for Youths – China (No. ZR2013HQ043).
    Introduction For almost a decade, non-vitamin K oral anticoagulants (NOAC) have expanded the choice of anticoagulation in patients with atrial fibrillation (AF). Currently, NOACs utilize two distinct molecular mechanisms of coagulation inhibition: Inhibition of factor IIa by dabigatran and inhibition of factor Xa by apixaban, edoxaban or rivaroxaban respectively. All NOACs feature a superior benefit/risk ratio in terms of bleeding, mortality and stroke prevention as compared to vitamin-k antagonists (VKA) (Connolly et al., 2009; Giugliano et al., 2013; Granger et al., 2011; Patel et al., 2011). For stroke prevention, the 2016 ESC guidelines recommend the use of NOAC over VKA. However, until now there are still no recommendations regarding the optimal type of NOAC for the individual patient. While many drug characteristics may be similar, the NOAC landmark trials have shown interesting results regarding patients' risk of myocardial infarction (MI): factor IIa inhibition by dabigatran was associated with increased risk of MI, whereas risk of MI was numerically lower as compared to VKA in the landmark trials testing factor Xa inhibiting NOACs (rivaroxaban, apixaban, edoxaban). In the context of these findings, potential underlying mechanisms have been proposed by basic and clinical science studies. To Gene family affect, this review will summarize the differences of MI risk between different NOACs and provide related mechanistic insights.
    Factor IIa inhibition and risk of myocardial infarction Dabigatran is a direct thrombin (factor IIa) inhibitor. In its landmark trial, RE-LY, both dose regimens of dabigatran (110 mg b.i.d. and 150 mg b.i.d.) were associated with an enhanced risk for MI (Connolly et al., 2009). Moreover, a meta-analysis of four randomized trials demonstrated a relative risk increment of 41% for the occurrence of MI under dabigatran compared to VKA (Artang, Rome, Nielsen, & Vidaillet, 2013). However, dabigatran still obtained a superior net clinical benefit compared to VKA. The recently published RE-DUAL PCI trial compared dabigatran Mevastatin (110 mg or 150 mg) and P2Y12-inhibition to triple therapy (warfarin, aspirin, P2Y12-inhibition) in patients with AF undergoing percutaneous coronary interventions (PCI) (Cannon et al., 2017). The results of this trial were awaited eagerly to help guide anticoagulation following PCI in patients with AF. Especially, as RE-LY reported the above mentioned enhanced risk of MI. Fewer bleeding events occurred in patients receiving dual therapy with dabigatran (110 mg and 150 mg). Although underpowered to detect differences in ischemic events, again, a numerically higher rate of MI was found in dabigatran treated patients especially in the low-dose regimen group. This numerical higher rate reached near statistical significance in the 110 mg but not in the 150 mg dabigatran intervention. This was remarkable, especially as the sample size of RE-DUAL PCI was substantially smaller than in RE-LY (RE-DUAL PCI: 2725 patients, RE-LY: 18,113 patients).