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  • br Conclusions Our in vitro and in vivo data collectively

    2021-10-15


    Conclusions Our in vitro and in vivo data collectively demonstrate that zifaxaban is effective in preventing thrombus formation via direct and specific inhibition of FXa in a dose-dependent manner. Furthermore, zifaxaban has a potency that is similar to that of rivaroxaban and shows a similar or lower risk of bleeding than rivaroxaban in this PFI-2 study. This demonstrates that zifaxaban has a good safety profile. Zifaxaban has potential for development as an improved FXa inhibitor for the prophylaxis and treatment of thrombotic diseases.
    Acknowledgements
    Cardiovascular diseases are the leading cause of death in developed countries, and most cardiovascular events are primarily due to thrombosis. Despite the extensive efforts to discover and develop new antithrombotic agents, warfarin remains the only approved oral anticoagulant in the United States. Other agents such as heparin and fondaparinux are available only by parenteral administration. Limitations of these agents have prompted extensive research for novel anticoagulants. Factor Xa (fXa) has been a major focus of pharmaceutical intervention in the past decade because of its central and unique position in the coagulation cascade. Significant progress has been made in the discovery and development of fXa inhibitors as anticoagulants. Several small molecule fXa inhibitors have been in phase III clinical trials. Among them the first oral fXa inhibitor, rivaroxaban, has recently been approved in both Europe and Canada for the prophylaxis of venous thromboembolism. Our efforts to discover and develop orally active inhibitors of fXa led to clinical candidates DPC423 (), razaxaban (), and apixaban () (). Razaxaban and apixaban were studied in phase II clinical trials and shown to be efficacious in the treatment of deep vein thrombosis. Apixaban, which has an overall better pharmacokinetic profile, is currently in phase III clinical trials for both venous and arterial indications. The discovery effort which ultimately led to apixaban significantly advanced our understanding of moieties that were sufficiently tolerated on the P phenyl group., As part of our efforts to further diversify the P portfolio, we discovered a novel phenyltriazolinone P moiety as shown in structures and . Herein we describe the synthesis and X-ray crystal structures of these potent and selective fXa inhibitors containing a phenyltriazolinone in the P position. The syntheses of compounds listed in , are shown in , , . The glycinamide was prepared from DPC423 in a two step manner. DPC423 was coupled to NBocGlycine and deprotected with TFA to afford compound . Compounds – were prepared from compound (). The cyano group in was readily converted to the triazolinone derivative by treatment with gaseous HCl in methanol, followed by treatment with semicarbazide/-methylmorpholine in dioxane at reflux. Using a similar but modified protocol, the aminothiadiazole and aminotriazole were also prepared as shown in . Triazolinones – were prepared in a similar fashion as shown in . Compound was synthesized according to the procedures described in Ref. . The cyano group was converted to triazolinone as described above. Suzuki coupling of with 2-formylphenylboronic acid (), followed by reductive amination with appropriate amines afforded compounds – in . Suzuki coupling of with 2-methylsulfonylphenylboronic acid () provided compound . Ullmann coupling of compound with imidazole gave compound , which was converted to triazolinone via methods described above. shows the synthesis for compound wherein the CF on the pyrazole was replaced with a carboxamide moiety. Compounds and were prepared according to the procedures described in Ref. . Reaction of and with triethylamine in refluxing toluene gave bicycle . The ester in compound was converted to the carboxamide to yield . Formation of the triazolinone followed by Suzuki reaction and reductive amination as described previously produced compound in .