Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor

Zhang, Penglie; Huang, Wenrong; Wang, Lingyan; Bao, Liang; Jia, Zhaozhong J.; Bauer, Shawn M.; Goldman, Erick A.; Probst, Gary D.; Song, Yonghong; Su, Ting; Fan, Jingmei; Wu, Yanhong; Li, Wenhao; Woolfrey, John; Sinha, Uma; Wong, Paul; Edwards, Susan; Arfsten, Ann; Clizbe, Lane A.; Kanter, James; Pandey, Anjali; Park, Gary; Hutchaleelaha, Athiwat; Lambing, Joseph L.; Hollenbach, Stanley J.; Scarborough, Robert M.; Zhu, Bing‐Yan

doi:10.1016/j.bmcl.2009.02.111

Cited by 94 publications

(61 citation statements)

References 44 publications

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“…It is interesting that betrixaban and eribaxaban, which are direct factor Xa inhibitors, were not ideal for preventing all-cause thrombosis or bleeding but provided advantages when treating major thrombosis and bleeding events. These drugs were potent, orally active and highly selective for factor Xa, and they were selected from a group of similar compounds because of their low affinity for the human ether-à-go-go-related gene (hERG) and showed favourable effectiveness for preventing PE in particular [140]. The U.S. Food and Drug Administration has granted a Fast Track designation to betrixaban for the extended-duration prevention of VTE in acutely ill patients.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta-Analysis

Wang¹,

Zheng²,

Zhao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Venous thromboembolism (VTE) is the most common complication after major joint surgery. VTE can easily develop into pulmonary embolism (PE), leading to cardiopulmonary dysfunction or sudden death. We aimed to comprehensively analyse the thromboprophylactic drugs that are used to prevent thrombosis and reduce bleeding risk. Methods: We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that evaluated the use of thromboprophylaxis after major joint surgery. The major outcomes were the numbers of all-cause VTE and bleeding events, and the secondary outcomes were major VTE and major bleeding/clinically relevant non-major bleeding events. A random-effects network meta-analysis was used to assess the effectiveness and tolerability of each anticoagulant after major joint surgery. Results: We included 104 trials that assessed 110,643 patients in our meta-analysis. The cluster ranking of major outcomes indicated that FXI-ASO, ardeparin, aspirin, and apixaban were ideal for preventing all-cause VTE and avoiding all bleeding events. Nadroparin, recombinant hirudin, and rivaroxaban effectively inhibited VTE but were associated with a high risk of bleeding. For secondary outcomes, we found that betrixaban, dalteparin, warfarin, and eribaxaban were ideal for preventing major VTE and reducing major bleeding, while rivaroxaban effectively inhibited major VTE but was associated with a high risk of major/clinically relevant non-major bleeding. A sensitivity analysis showed that the effect of apixaban was more robust for major outcomes, while aspirin was more robust for preventing all-cause bleeding events. In secondary outcomes, the effect of warfarin was more robust, while apixaban was still considered an ideal treatment to inhibit major VTE and bleeding events. Conclusion: Our study indicates that FXI-ASO, ardeparin, aspirin, and apixaban are ideal for preventing all-cause VTE and reducing all bleeding events, among which apixaban is the most reliable. Betrixaban, dalteparin, warfarin, and eribaxaban are ideal for preventing major VTE and reducing major/clinically relevant non-major bleeding events, among which warfarin is the most reliable.

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Section: Discussionmentioning

confidence: 99%

Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta-Analysis

Wang¹,

Zheng²,

Zhao³

et al. 2017

Cell Physiol Biochem

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“…Wegen der kanzerogenen Eigenschaften von Chloranilin wurde sie durch Chlorpyridin ersetzt. Diese Gruppe ist Bestandteil von Betrixaban (29), [62] einem Entwicklungskandidaten von Portola/ Merck (US). An analogen Derivaten wurde gezeigt, dass die Chlorpyridyleinheit nicht nur die Cl-p-Wechselwirkung mit …”

Section: Faktor-xa-inhibitorenunclassified

“…[45] Die Arbeiten zu Betrixaban zeigten, dass Chloranthranilamidgruppen im Mittelteil des Inhibitormoleküls eine signifikante hERG-Inhibition verursachen. Erst der Ersatz des Chloratoms durch eine weniger lipophile Methoxygruppe ermöglichte mit einer 16-fach verringerten hERGInhibition die Durchführung klinischer Studien; [62] viele andere Derivate bedurften aber einer innermolekularen Kompensation der positiven Ladung durch eine Carboxylatgruppe. [45] Umfangreiche Arbeiten wurden bei Daiichi durchgeführt und waren Gegenstand mehrerer zum Teil über 1000-seitiger Patentanmeldungen [46] und Publikationen.…”

Section: Angewandte Chemieunclassified

“…Infrage kommen hierfür z. B. Methylsulfonylbenzol (DPC423), Pyridin-N-oxid (Otamixaban), Pyridine, Pyrrolopyridine, [58] Tetrahydro-5-methylthiazolo [5,4-c]pyridin (Edoxaban), Pyrazole und Imidazole sowie nichtaromatische Amide, Lactame (Apixaban), Morpholinone (Rivaroxaban), Pyridone (Eribaxaban), cyclische Amine, [59] Methylpiperazin, [60] Methylaminooxazoline und -imidazole, [61] Oxazolidinimine, Amidine (Betrixaban) [62] und Guanidine.…”

Section: Angewandte Chemieunclassified

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Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

2011

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Bislang müssen sich Patienten zur Vorbeugung von Thrombosen nach Operationen täglich Heparin spritzen oder müssen zur Schlaganfallprophylaxe bei Vorhofflimmern Vitamin‐K‐Antagonisten vom Cumarintyp einnehmen, die eine geringe therapeutische Breite haben und deren Dosierung regelmäßig überwacht werden muss. Um den Therapiestandard bei thromboembolischen Erkrankungen, wie tiefen Venenthrombosen, Lungenembolien und Hirnschlag bei Vorhofflimmern, zu verbessern, wurde in der letzten Dekade intensiv an neuen, oral wirksamen Thrombin‐ und Faktor‐Xa‐Inhibitoren geforscht. Einige dieser Verbindungen sind bereits auf dem Markt oder befinden sich in fortgeschrittener klinischer Entwicklung; sie könnten den Antikoagulantienmarkt revolutionieren.

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“…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. This review will focus on the development of dabigatran (Hauel et al, 2002), the first new oral anticoagulant (NOAC) to gain market approval for long-term indications 50 years after introduction of warfarin.…”

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 betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor

Cited by 94 publications

References 44 publications

Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta-Analysis

Effectiveness and Tolerability of Anticoagulants for Thromboprophylaxis after Major Joint Surgery: a Network Meta-Analysis

Orale, direkte Thrombin‐ und Faktor‐Xa‐Hemmer: Kommt die Ablösung für Warfarin, Blutegel und Schweinedärme?

The Discovery of Dabigatran Etexilate

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