Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties

Pinto, Donald; Galemmo, Robert A.; Quan, Mimi L.; Orwat, Michael J.; Clark, C. G.; Li, Renhua; Wells, Brian L.; Woerner, Francis J.; Alexander, Richard; Rossi, Karen A.; Smallwood, Angela; Wong, Pancras C.; Luettgen, Joseph M.; Knabb, Robert M.; He, Kan; Wexler, Ruth R.; Lam, Patrick Y.S.

doi:10.1016/j.bmcl.2006.08.027

Cited by 38 publications

(31 citation statements)

References 26 publications

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“…The enzyme activities of factor Xa, ␣-thrombin, and trypsin were determined as described previously (Pinto et al, 2007;Wong et al, 2008). In brief, the final concentration of human factor Xa, human ␣-thrombin, or human pancreatic trypsin in the assays was 0.1, 0.125, and 0.625 nM, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…1) is an oral anticoagulant in latestage clinical development for the prevention and treatment of venous thromboembolism, stroke prevention in atrial fibrillation, and secondary prevention in acute coronary syndrome. It is a potent, oral, reversible, selective, and direct factor Xa inhibitor, which inhibits both free and prothrombinase-bound factor Xa activity, and shows considerable efficacy in the prevention of arterial and venous thrombosis at doses that preserved hemostasis in rabbits (Pinto et al, 2007;Wong et al, 2008). It is also effective and safe for the prevention and treatment of venous thrombosis in humans (Lassen et al, 2007;Büller et al, 2008).…”

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confidence: 99%

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Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison

Wang¹,

Raghavan²,

He³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Apixaban, a potent and highly selective factor Xa inhibitor, is currently under development for treatment of arterial and venous thrombotic diseases. The O-demethyl apixaban sulfate is a major circulating metabolite in humans but circulates at lower concentrations relative to parent in animals. The aim of this study was to identify the sulfotransferases (SULTs) responsible for the sulfation reaction. Apixaban undergoes O-demethylation catalyzed by cytochrome P450 enzymes to O-demethyl apixaban, and then is conjugated by SULTs to form O-demethyl apixaban sulfate. Of the five human cDNA-expressed SULTs tested, SULT1A1 and SULT1A2 exhibited significant levels of catalytic activity for formation of O-demethyl apixaban sulfate, and SULT1A3, SULT1E1, and SULT2A1 showed much lower catalytic activities. In human liver S9, quercetin, a highly selective inhibitor of SULT1A1 and SULT1E1, inhibited O-demethyl apixaban sulfate formation by 99%; 2,6-dichloro-4-nitrophenol, another inhibitor of SULT1A1, also inhibited this reaction by >90%; estrone, a competitive inhibitor for SULT1E1, had no effect on this reaction. The comparable K m values for formation of O-demethyl apixaban sulfate were 41.4 M (human liver S9), 36.8 M (SULT1A1), and 70.8 M (SULT1A2). Because of the high level of expression of SULT1A1 in liver and its higher level of catalytic activity for formation of O-demethyl apixaban sulfate, SULT1A1 might play a major role in humans for formation of O-demethyl apixaban sulfate. O-Demethyl apixaban was also investigated in liver S9 of mice, rats, rabbits, dogs, monkeys, and humans. The results indicated that liver S9 samples from dogs, monkeys, and humans had higher activities for formation of O-demethyl apixaban sulfate than those of mice, rats, and rabbits.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison

Wang¹,

Raghavan²,

He³

et al. 2009

Drug Metab Dispos

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“…Preclinical studies have shown that apixaban was absorbed well in chimpanzees, dogs, and rats; the mean oral bioavailability was 51%, 88%, and 34%, respectively (Shantsila & Lip, 2008). In a rabbit arteriovenous shunt model, apixaban inhibited thrombus formation in a dose-dependent manner (Pinto et al, 2007).…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

Mavrakanas

Bounameaux

2011

Pharmacology & Therapeutics

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Thromboembolic disorders are among the major causes of morbidity and mortality, and anticoagulation remains the cornerstone of prevention and treatment of these disorders. Although effective, the well-established agents have significant drawbacks. Heparin, low molecular weight heparin, and fondaparinux must be given parenterally, which is inconvenient for long-term or home use. The orally administered vitamin K antagonists (such as warfarin) have a slow onset of action, thus requiring bridging therapy with a parenteral agent when immediate anticoagulation is needed (e.g. inpatients with acute deep vein thrombosis). Because vitamin K antagonists produce a variable anticoagulant response as a result of multiple drug-drug and food-drug interactions and genetic polymorphisms, frequent coagulation monitoring and dose adjustment are required to ensure a therapeutic level of anticoagulation, which is inconvenient for both patients and physicians. In the search for new agents to overcome the drawbacks associated with traditional agents, direct Factor Xa inhibitors (e.g. rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors (e.g. dabigatran etexilate) have been developed and are undergoing late-stage clinical evaluation for the prevention and treatment of thromboembolic disorders. These new oral agents have already shown promise in large-scale clinical studies and data suggest that we have entered a new era with novel drugs that are closer than ever to the 'ideal anticoagulant'. Because these new oral agents have a rapid onset of action and can be given at fixed doses without the need for routine coagulation monitoring, they may simplify treatment paradigms and are expected to improve overall clinical outcome

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“…In 2004 a new DTI ximelagatran (AstraZeneca; Gustafsson et al, 2004) gained approval in several countries for short-term anticoagulation treatment after orthopedic surgery, but was later withdrawn due to hepatotoxicity reports. Other companies concentrated their research activities on discovering FXa inhibitors (Pinto et al, 2010) including two recently approved FXa inhibitors -rivaroxaban and apixaban for treatment and prevention of VTE after orthopedic surgery (Pinto et al, 2007;Perzborn et al, 2011) and stroke prevention in atrial fibrillation Patel et al, 2011). Two additional FXa inhibitors, edoxaban (Furugohri et al, 2008) and betrixaban (Zhang et al, 2009), are completing Phase III trials.…”

Section: Introductionmentioning

confidence: 99%

The Discovery of Dabigatran Etexilate

Hauel

Clemens

Nar

et al. 2012

Analogue‐Based Drug Discovery III

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Thromboembolic disease is a major cause of mortality and morbidity in the developed world and is caused by an excessive stimulation of coagulation.Thrombin is a key serine protease in the coagulation cascade and numerous efforts have been made to develop safe and effective orally active direct thrombin inhibitors (DTIs). Current anticoagulant therapy includes the use of indirect thrombin inhibitors (e.g., heparins, low-molecular-weight-heparins) and vitamin K antagonists such as warfarin. However there are several caveats in the clinical use of these agents including narrow therapeutic window, parenteral delivery, and foodand drug-drug interactions. Dabigatran is a synthetic, reversible DTI with high affinity and specificity for its target binding both free and clot-bound thrombin, and offers a favorable pharmacokinetic profile. Large randomized clinical trials have demonstrated that dabigatran provides comparable or superior thromboprophylaxis in multiple thromboembolic disease indications compared to standard of care. This minireview will highlight the discovery and development of dabigatran, the first in a class of new oral anticoagulant agents to be licensed worldwide for the prevention of thromboembolism in the setting of orthopedic surgery and stroke prevent in atrial fibrillation.

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Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties

Cited by 38 publications

References 26 publications

Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison

Sulfation of O-Demethyl Apixaban: Enzyme Identification and Species Comparison

The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism

The Discovery of Dabigatran Etexilate

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