In vivo Evaluation of DX-9065a, a Synthetic Factor Xa Inhibitor, in Experimental Vein Graft

Kim, Dong Ik; Kambayashi, Jun-ichi; Shibuya, Takashi; Sakon, M.; Kawasaki, Tomio

doi:10.5551/jat1994.2.110

Cited by 13 publications

(8 citation statements)

References 18 publications

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“…A direct comparison of DX-9065a with heparin and the thrombin inhibitor argatroban showed that the efficacy of DX-9065a was equivalent to argatroban, and superior to heparin in preserving vessel patency [104]. An additional comparison with warfarin concluded that DX-9065a had fewer side effects at doses that inhibited thrombus formation [105].…”

Section: Incorporation Of Less Basic P1 Elementsmentioning

confidence: 97%

Perspectives on Factor Xa Inhibition

Rai¹,

Sprengeler²,

Elrod³

et al. 2001

CMC

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Blood coagulation involves a complex cascade of enzymatic reactions, ultimately generating fibrin, the basis of all blood clots. This cascade is comprised of two arms, the intrinsic and extrinsic pathways which converge at factor Xa to form the common pathway. Factor Xa activates prothrombin to thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin. Recently, both natural and synthetic factor Xa inhibitors have shown promising pharmacological effects in animal models of thrombosis. Accordingly, factor Xa has emerged as a compelling target for pharmacological intervention and much recent effort has focused on selective and potent inhibition of this key enzyme. Factor Xa and other enzymes in the coagulation cascade belong to the trypsin-like serine protease family, the various members of which are involved in numerous physiological functions in the body. Hence, to avoid toxicity and adverse side effects, it is important to selectively inhibit the target enzyme. Achieving the needed selectivity has proved challenging due to the high degree of structural homology around the active site of this class of enzymes. This article provides a brief review of the strategies currently being employed to develop oral anticoagulants and, more specifically, the structural features of protein-ligand binding that have been utilized to achieve potency and selectivity toward factor Xa. Additionally, selected lead molecules will be discussed to highlight binding motifs used to attain both potency and selectivity in drug candidates.

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Section: Incorporation Of Less Basic P1 Elementsmentioning

confidence: 97%

Perspectives on Factor Xa Inhibition

Rai¹,

Sprengeler²,

Elrod³

et al. 2001

CMC

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“…Its antithrombotic efficacy has been shown in animal models of disseminated intravascular coagulation, 12 venous thrombosis, 13,14 arteriovenous shunt thrombosis, 14,15 and vein graft thrombosis. 16 When given to healthy male volunteers, DX-9065a has been well tolerated, with no serious adverse events or clinically significant changes in routine laboratory assessments or bleeding time. 17,18 DX-9065a exhibits renal clearance, 17 and, in a study of single, increasing, intravenous doses of DX-9065a, peak plasma concentrations reached 1640 ng/mL in subjects receiving 30 mg over a period of 1 hour.…”

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confidence: 95%

First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

et al. 2002

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Background-Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa. Methods and Results-In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (rϭ0.97), prothrombin time (rϭ0.77), and international normalized ratio (rϭ0.72) but less so with activated partial thromboplastin time (rϭ0.56; all PϽ0.001). Conclusions-This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

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“…Its antithrombotic efficacy and safety has been shown in animal models of disseminated intravascuar coagulation, venous thrombosis, vein graft thrombosis and arterial thrombosis and thrombolysis [79][80][81][82][83][84]. In addition DX-9065a has been given orally in rats and it was found to be effective and well tolerated [85].…”

Section: Dx-9065amentioning

confidence: 95%

Heterogeneity of Synthetic Factor Xa Inhibitors

Gerotziafas

Samama²

2005

CPD

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Heparins and vitamin K antagonists are the landmarks of antithrombotic treatment. Both of them were discovered by serendipity; they are multi-targeted drugs and share several limitations. New molecules have been designed in order to be both more selective concerning their biological target and more homogeneous in their biochemical structure aiming at an improved benefit/risk ratio in the treatment of thrombotic disease. In this article, we will review the pharmacological characteristics of the new synthetic direct or antithrombin dependent inhibitors of FXa in the light of the modern concept of blood coagulation process. We will also present the most recent data from the clinical trials with synthetic inhibitors of FXa. Among them, the synthetic pentasaccharide fondaparinux is the first synthetic and specific FXa inhibitor, which has been approved by health authorities in Europe and in the USA for the prophylaxis of venous thromboembolism in major orthopaedic surgery and is being approved for the treatment of pulmonary embolism and DVT as a single daily subcutaneous injection. The phase II dose-finding trial of the "meta-pentasaccharide" idraparinux administered subcutaneously once weekly in the secondary prevention of VTE has been completed. DX-9065a is the first direct synthetic inhibitor which has been studied in patients with coronary disease. Razaxaban, BAY59-7939, ZK-807834 and JTV-803 are orally active direct FXa inhibitors, which have been studied in phase II trials. Several other synthetic direct inhibitors of FXa (such as FXV673, YM60828, KFA-1411) are in a pre-clinical stage of research. From a clinical point of view, the results of recent trials with the synthetic specific FXa inhibitors clearly show that the inhibition of FXa is a critical point in the antithrombotic strategy.

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In vivo Evaluation of DX-9065a, a Synthetic Factor Xa Inhibitor, in Experimental Vein Graft

Cited by 13 publications

References 18 publications

Perspectives on Factor Xa Inhibition

Perspectives on Factor Xa Inhibition

First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

Heterogeneity of Synthetic Factor Xa Inhibitors

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