Factor X inhibitors

Factor X plays a central role in coagulation, being the point of convergence of the extrinsic and intrinsic pathways of blood clotting. It may also act as one of the links between the coagulation and inflammatory pathways. These findings suggest that factor X may represent an attractive target for a new antithrombotic drug. Indeed, a factor X inhibitor, fondaparinux, has already been approved for clinical use to prevent post-operative deep vein thrombosis. Factor X inhibitors are also being evaluated for use in the treatment of the acute coronary syndromes, pulmonary embolism and deep vein thrombosis. Oral factor X inhibitors are also being developed, which may be of use in the outpatient prevention and/or treatment of stroke and thromboembolism.     

Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1)

Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.     

The use of antibodies to coagulation factors for anticoagulant therapy

Current treatments for preventing thrombotic diseases are associated with a significant risk of bleeding. Improved anticoagulant agents are therefore still required. The specificity and pharmacokinetics properties of monoclonal antibodies to coagulation factors allow novel anticoagulation approaches. Treatment with human antibodies or humanized mouse monoclonal antibodies should avoid unacceptable side effects due to immune response to the drug. Such antibodies were developed against three coagulation factor: Tissue factor (TF), Factor IX (FIX) and Factor VIII (FVIII). A fully humanized antibody was successfully derived from a mouse monoclonal antibodies to TF. In vivo studies with monoclonal antibodies to TF demonstrated efficient antithrombotic activity. Anti-TF antibodies may also prove useful in cardiovascular disorders and cancer, given the role of TF in these diseases. Mouse and human monoclonal antibodies to FIX were also efficient to prevent thrombosis in animal models of venous and arterial thrombosis and in stroke. A humanized anti-FIX antibody was tested in phase I study in healthy volunteers. The pharmacokinetics of the antibody were determined by the rapid formation of stable complexes with newly synthesised FIX. Human anti-FVIII antibodies inhibiting only partially FVIII activity were recently described. Investigations in mice have established that treatment with such anti-FVIII antibodies is efficient to prevent deep vein thrombosis. Given the low concentration of FVIII in plasma and the long half-life of antibody, treatment with anti-FVIII antibody could be very convenient, allowing one administration every month. Altogether, monoclonal antibodies to coagulation factor appear as promising novel antithrombotic drugs.     

New anticoagulants for venous thromboembolic disease

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. In the US, approximately 260000 cases are diagnosed annually. Current drugs for the prevention and treatment of venous thromboembolism (VTE) include heparin, low-molecular-weight heparins and warfarin. Since they possess several disadvantages, researchers are investigating improved anticoagulants. To understand how any promising anticoagulant would work, a review of the pathophysiology and regulation of the coagulation cascade is provided. The more prominent drugs reviewed include tissue factor pathway inhibitor protein, nematode anticoagulant protein, Factor IX inhibitors, anti-Factor Xa inhibitors (DX-9065a (Daiichi Seiyaku Co Ltd), YM-60828 (Yamanouchi Pharmaceutical Co Ltd), fondaparinux, idraparinux (Sanofi-Synthelabo/NV Organon)), selective thrombin inhibitors (oral heparin, ximelagatran (AstraZeneca plc)) and enhancers of natural anticoagulants (activated protein C, ART-123 (Asahi Kasei Pharma Corp)).     

Small molecule coagulation cascade inhibitors in the clinic

Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. For several decades, anticoagulant options for the treatment and prevention of thrombosis have been limited mainly to agents such as unfractionated heparin and oral vitamin K antagonists such as warfarin. Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clinical practice. A variety of novel anticoagulants with improved pharmacologic and clinical profiles are in development, offering benefits over traditional therapies. Specifically, progress has been made in the development of small molecule Factor Xa inhibitors and thrombin inhibitors. The most advanced drugs reviewed include DPC-423, DPC-602, razaxaban, GSK's 813893, Portola's Xa inhibitors (formerly Millennium), otamixaban, DU-176b, KFA-1982, BAY-59-7939, DX-9065a, YM-150, LY-517717, Exanta, 3DP's thrombin inhibitors, SSR-182289, LB-30057, LB-30870, BIBR-1048 and Merck's thrombin inhibitors. With their potentially consistent and predictable pharmacological profile, oral formulation, and decreased need for coagulation monitoring, these new agents will likely increase the use and duration of anticoagulation treatment in thromboembolic disorders and reduce the burden associated with long-term management.     

Fondaparinux

Fondaparinux is the first drug from the pentassaccharide factor X inhibitor class of anticoagulants to be approved for clinical use. It has been shown to be effective in the prevention of deep vein thrombosis in patients undergoing major orthopaedic surgery of the lower limbs. The drug is also being evaluated for use in the acute coronary syndromes and established thromoboembolic events. The pharmacology of fondaparinux is discussed in this review, as well as the major clinical trials involving this drug. Arguments for (and against) the use of this drug are also summarised.     

凝血Xa因子直接抑制剂的研究进展与临床应用评价

目的：抗凝治疗是心房颤动药物治疗的核心,但鉴于目前临床应用的传统抗凝血药存在的局限性,一类起效快速、选择性高、作用直接抑制凝血Xa因子的药物应运而生,为临床抗凝治疗提供了更多的选择。本文总结凝血Xa因子直接抑制剂的研究进展与临床评价。方法：采用国内、外文献分析方法。结果与结论：相对于华法林而言,凝血Xa因子直接抑制荆可更特异地抑制血栓形成,抗凝作用起效快,无需监测凝血指标和调整剂量,所致出血风险低,使抗凝作用由多靶点向单靶点迈进,成为临床一线重要的抗凝血药。     

Clinical and Experimental Experience with Factor Xa Inhibitors

Cardiovascular disease is the major cause of mortality in the industrial world today. We are constantly moving towards new and better ways of fighting this epidemic. Advances have been made in various fields such as patient education, imaging techniques, interventional cardiology, and novel therapeutic agents. In particular, antithrombotics are being studied with great interest and hope. Amid this class of agents, factor Xa inhibitors have already begun to show promising results in trials involving patients with acute coronary syndromes. Whereas DX-9065a is in late stage clinical trials, fondaparinux sodium is available for clinical use. Promising results have been obtained with fondaparinux sodium in patients with coronary artery disease in the PENTUA (Pentasaccharide in Unstable Angina) and PENTALYSE (Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction) trials. Besides having a direct effect on the coagulation cascade, they have shown properties that indirectly influence the remodeling of plaques in the coronary circulation. Available evidence on factor Xa inhibitors does not ensure a remedy to acute coronary syndromes but it gives hope of improving current treatments and reducing the morbidity and mortality of cardiovascular disease.The efficacy and tolerability of fondaparinux sodium in the prevention and treatment of deep vein thrombosis (with or without pulmonary embolism) has been established in several large trials such as PENTATHLON (Pentasaccharide in Total Hip Replacement Surgery), PENTAMAKS (Pentasaccharide in Major Knee Surgery), EPHESUS (European Pentasaccharide Hip Elective Surgery), PENTHIFRA (Pentasaccharide in Hip-Fracture Surgery), and PENTHIFRA-Plus. Whereas fondaparinux sodium offers benefits over low molecular weight heparins and unfractionated heparin, the incidence of bleeding complications was greater with fondaparinux sodium than with unfractionated heparin. Treatment with factor VIIa can reverse the anticoagulant effect of fondaparinux sodium and this may be particularly important in patients who need to undergo emergency surgical procedures. Fondaparinux sodium has been recently approved for use, in conjunction with warfarin, in patients with symptomatic deep vein thrombosis or acute pulmonary embolism based on the results of two large trials conducted by the Matisse investigators. In conclusion, these observations strongly suggest the clinical potential of this class of agents in preventing arterial and venous thrombosis.     

应用利伐沙班预防人工髋关节置换术后下肢深静脉血栓形成的疗效观察

目的 探讨应用口服利伐沙班预防人工髋关节置换术后下肢深静脉血栓形成的临床疗效.方法 所有人工髋关节术后的患者,在术后6h开始口服利伐沙班10mg,1次/d,连续10d.结果 所有口服利伐沙班的人工髋关节置换术后的患者,术后无患肢肿胀、疼痛、活动受限的发生,经术后下肢彩色多普勒检测,无1例发生下肢深静脉血栓.结论 利伐沙班是一种高选择性抑制凝血因子Xa的口服抗凝药物,术后早期应用,具有良好的安全性和有效性,临床使用方便,效果显著.     

Contribution of in vivo models of thrombosis to the discovery and development of novel antithrombotic agents

Cardiovascular and cerebrovascular diseases continue to be the leading cause of death throughout the world. Over the past two decades, great advances have been made in the pharmacological treatment and prevention of thrombotic disorders (e.g., tissue plasminogen activators, platelet GPIIb/IIIa antagonists, ADP receptor antagonists such as clopidogrel, low-molecular weight heparins, and direct thrombin inhibitors). New research is leading to the next generation of antithrombotic compounds such as direct coagulation FVIIa inhibitors, tissue factor pathway inhibitors, gene therapy, and orally active direct thrombin inhibitors and coagulation Factor Xa (FXa) inhibitors. Animal models of thrombosis have played a crucial role in discovering and validiting novel drug targets, selecting new agents for clinical evaluation, and providing dosing and safety information for clinical trials. In addition, these models have provided valuable information regarding the mechanisms of these new agents and the interactions between antithrombotic agents that work by different mechanisms. This review briefly presents the pivitol preclinical studies that led to the development of drugs that have proven to be effective clinicallly. The role that animal models of thrombosis are playing in the discovery and development of novel antithrombotic agents is also described, with specific emphasis on FXa inhibitors. The major issues regarding the use of animal models of thrombosis, such as the use of positive controls, appropriate pharmacodynamic markers of activity, safety evaluation, species-specificity, and pharmacokinetics, are highlighted. Finally, the use of genetic models in thrombosis/hemostasis research and pharmacology is presented using gene-therapy for hemophilia as an example of how animal models have aided in the development of these therapies that are now being evaluated clinically. In summary, animal models have contributed greatly to the discovery of currently available antithrombotic agents and will play a primary role in the discovery and characterization of the novel antithrombotic agents that will provide safe and effective pharmacological treatment for life-threatening thrombotic diseases.     

Inhibition of Factor Xa

Anticoagulant therapy plays an important role in the prevention and treatment of pathologic arterial and venous thrombosis. There is increasing enthusiasm in the inhibition of Factor Xa as a target to achieve therapeutic anticoagulation because of its central and 'upstream' position in the coagulation process. The indirect, selective, parenteral Factor Xa inhibitor fondaparinux sodium (synthetic pentasaccharide) has been studied extensively in the prevention and treatment of venous thromboembolism. In an overview of four studies in patients undergoing major orthopedic surgery, fondaparinux sodium was associated with a 55% reduction in recurrent thromboembolism, albeit with a modest increase in bleeding. Preliminary results from phase II studies of fondaparinux sodium in patients with ST-elevation and non-ST-elevation acute coronary syndromes have been promising and have led to the initiation of two large phase III trials, which are currently underway. Idraparinux sodium, a long-acting synthetic pentasaccharide, is currently being investigated as a once-weekly alternative to other long-term anticoagulants. DX-9065a and razaxaban are two of many direct selective Factor Xa inhibitors currently in development. DX-9065a has been studied in phase II trials in patients undergoing percutaneous coronary intervention and in those with non-ST-elevation acute coronary syndromes. Razaxaban has been studied in a phase II trial in patients who have undergone orthopedic surgery. Data from these trials, although preliminary and based on small numbers of patients, suggest that direct selective Factor Xa inhibition may provide effective anticoagulation, perhaps without excessive bleeding. Inhibition of Factor Xa is a promising target for the prevention and treatment of thrombosis in both the venous and arterial circulation. Ongoing investigation with numerous oral and parenteral inhibitors of Factor Xa will establish the potential of Factor Xa as a target for therapeutic anticoagulation.     

Off label use in long-term anticoagulation after liver transplantation due to phenprocoumon-induced hepatic failure

BACKGROUND: Drug therapy should be individualised according to criteria of efficacy, adverse effects, and treatment adherence. This is particularly important at the interface of inpatient and ambulatory care. Aspects of drug approval (labelling) and individual refunding by health care insurances should also be taken into account. CASE REPORT: A patient (male, 61, painter) showed elevated transaminases after treatment with phenprocoumon because of a deep vein thrombosis in 1999. Transaminases normalized completely after discontinuation of excluded. After a recurrent thrombosis in 2003 phenprocoumon was prescribed again followed by recurrent elevation of transaminases and subsequent cholestatic hepatitis progressing to fulminant hepatic failure that required liver transplantation. After transplantation the patient's general state of health was good and liver function nearly normal. Anticoagulation was indicated beyond the postoperative phase because of recurrent deep vein thrombosis and atrial fibrillation. A low molecular weight heparin was chosen for long-term treatment. CONCLUSION: A low molecular weight heparin appears to be the most appropriate way to maintain effective and safe anticoagulation in this patient. Coumarins carry a residual risk of an extrahepatic, immunologically mediated cross sensitization. Long-term use of ximelagatran (which has been withdrawn meanwhile) may also cause liver damage. For heparinoids, hirudines, and other drugs affecting coagulation like platelet aggregation inhibitors, therapeutic evidence is not sufficient. Though subcutaneous application of heparin is a disadvantage for the patient, therapeutic alternatives do not have better documented efficacy or less hepatotoxic potential. The low molecular weight heparin fulfils the criteria for refunding set by federal jurisdiction.     

Perspectives on factor Xa inhibition

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.     

新一代口服直接凝血酶因子Ⅱa抑制剂AZD0837

凝血因子Ⅱ在凝血级联反应中处于下游的关键位置,被激活后形成凝血酶而催化纤维蛋白原产生纤维蛋白导致凝血,因此其为血栓形成的关键因素。抑制凝血酶可以延长凝血时间,减少血栓形成风险。英国AstraZeneca公司研发的新一代口服直接凝血酶因子Ⅱa抑制剂AZD0837可用于治疗和预防心房颤动引起的卒中和深静脉血栓的发生。目前已经公布的临床前、临床Ⅰ期和Ⅱ期实验数据显示,其具有优于华法林的治疗效果,因此具有巨大的市场潜力。     

探讨深静脉栓塞患者凝血纤溶指标的变化及临床意义

目的观察深静脉栓塞（DVT）患者血浆中凝血纤溶指标的变化,并探讨其临床意义。方法分别对35例深静脉栓塞患者和35例健康者血浆（对照组）,测定其凝血酶原时间（PT）、活化部分凝血酶时间（APTT）、纤维蛋白原（FIB）、凝血酶时间（TT）、D-二聚体（D—dimer）和纤维蛋白（原）降解产物（FDP）,并与对照组进行比较。结果深静脉栓塞患者PT、FIB、TT、D-dimer和FDP与正常对照组比较有显著性差异（P（0．01）,APTT延长不超过10秒,与对照组比较无显著性差异（P〉0．01）。结论深静脉栓塞患者血液存在明显的凝血纤溶系统的异常,在血栓形成过程机体呈高凝状态,血栓形成后机体继发纤溶亢进,各项指标可作为DVT患者安全、有效的筛查试验,D-二聚体和FDP对DVT的临床早期诊断和治疗监测及避免发生并发症有重要价值。     

Factor Xa inhibitors

Summary Factor Xa is the serine protease that activates prothrombin to yield thrombin. Inhibitors of factor Xa play a crucial role in curtailing thrombin generation. Two key factor Xa inhibitors that are found in blood are antithrombin III and tissue factor pathway inhibitor. Inhibition of factor Xa is a mechanism that is also exploited by certain hematophagous animals to facilitate feeding. Evaluation of tick anticoagulant peptide (TAP) and leech-derived antistasin (ATS) using animal models of thrombotic disorders has confirmed that specific blockade of factor Xa activity is an effective antithrombotic strategy. Several laboratories are currently pursuing low-molecular weight synthetic factor Xa inhibitors for use as anticoagulants in the treatment and/or prevention of thrombosis.     

CTC-11 (Teijin)

Teijin and Chemo-Sero are codeveloping CTC-111 as a treatment for disseminated intravascular coagulation (DIC) due to protein C deficiency. The drug was launched for the treatment of protein C deficiency in Japan on January 31, 2001 and as of October 2001 was awaiting approval for the treatment of DIC, also in Japan [426762]. CTC-111 was evaluated in a multicenter pharmacokinetic trial in venous thrombosis patients with inherited protein C deficiency. CTC-111 was effective in six of ten patients with venous thrombosis, six of seven patients with deep vein thrombosis and two of three patients with pulmonary embolism. Treatment was safe and effective and there were no serious adverse events [350149].     

Apixaban, an oral, direct inhibitor of activated Factor Xa

Apixaban is an oral, direct Factor Xa inhibitor that is being developed by Bristol-Myers Squibb Co and Pfizer Inc. Apixaban is currently undergoing phase III clinical trials for cerebrovascular ischemia, deep vein thrombosis and lung embolism, and phase II clinical trials for coronary artery disease.     

New Anticoagulants

Arterial and venous thrombosis are a major cause of morbidity and mortality. Anticoagulants are a cornerstone of treatment in patients with these disorders. The two most frequently used anticoagulants, heparin and warfarin, have pharmacological and/or biophysical limitations that make them difficult to use in day-to-day clinical practice. Development of new anticoagulants, which were designed to overcome these limitations, has been facilitated by an increased understanding of the coagulation cascade, the advent of molecular modeling and structure-based drug design, and the realization that the treatment of thrombosis and its complications consumes billions of dollars in annual healthcare expenditures. New anticoagulants target various steps in the coagulation pathway. Coagulation is triggered by the factor VIIa/tissue factor complex and propagated by factors Xa and IXa, together with their activated cofactors, factor Va and VIIIa, respectively. Thrombin, the final effector in coagulation, then converts soluble fibrinogen into insoluble fibrin, the major matrix protein of the clot. New anticoagulation drugs that target each of these clotting enzymes have been developed. This review will focus on those drugs in more advanced stages of clinical evaluation. These include inhibitors of initiation of coagulation (tissue factor pathway inhibitor, nematode anticoagulant peptide and active-site blocked factor VIIa), inhibitors of propagation of coagulation (active-site blocked factor IXa, antibodies against factor IX/IXa, fondaparinux sodium, direct factor Xa inhibitors, protein C derivatives and soluble thrombomodulin), and thrombin inhibitors (hirudin, bivalirudin, argatroban and ximelagatran).     

中西药预防人工髋关节术后深静脉血栓形成的效果研究

目的 分析中西药预防人工髋关节术后深静脉血栓形成的临床效果。方法 收集2011年1月～2013年6月本院收治的人工髋关节术患者,遵循随机原则,将患者分为Ⅰ组与Ⅱ组,每组各60例。Ⅰ组在基础预防上加中药血栓通注射液预防深静脉血栓,Ⅱ组加西药低分子肝素钠针剂预防治疗,分析两组患者的临床预防效果。结果 两组患者DVT发病率差异无统计学意义（P〉0．05）。两组患者术后出血量、术后引流量及切开血肿、延迟愈合等并发症,差异有统计学意义（P〈0．05）。两组患者术前APTT差异无统计学意义（P〉0．05）。术后1、2周,两组患者APTT差异有统计学意义（P〈0．05）。术前及术后1、2周,两组患者PT、INR及PLT等凝血指标,差异无统计学意义（P〉0．05）。结论 采取中药血栓通与西药低分子肝素钠预防人工髋关节术后深静脉血栓形成．其有效性相似．可降低深静脉血栓发生率,且术后出血风险及切口并发症发生率较低分子钠组明显低,安全性高,故采取中药血栓通预防人工髋关节术后深静脉血栓形安全有效。