Discovery of 1-(3‘-Aminobenzisoxazol-5‘-yl)-3-trifluoromethyl-<i>N</i>-[2-fluoro-4- [(2‘-dimethylaminomethyl)imidazol-1-yl]phenyl]-1<i>H</i>-pyrazole-5-carboxyamide Hydrochloride (Razaxaban), a Highly Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor

Quan, Mimi L.; Lam, Patrick Y.S.; Han, Qi; Pinto, Donald; He, Ming; Li, Renhua; Ellis, Christopher D.; Clark, C. G.; Teleha, Christopher A.; Sun, Jung‐Hui; Alexander, Richard; Bai, Steve; Luettgen, Joseph M.; Knabb, Robert M.; Wong, Pancras C.; Wexler, Ruth R.

doi:10.1021/jm0497949

Cited by 183 publications

(76 citation statements)

References 22 publications

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“…Based on 65, a series of aminobenzisoxazoles, represented by 71 (fXa K i 5 0.09 nM, fIIa K i 5 6,300 nM, trypsin K i 45,200 nM), was evaluated. 145,146 However, 71 showed poor permeability, poor solubility, and low oral bioavailability (2% in dog). More basic and water-soluble moieties were incorporated into the terminal group on P4 in order to improve the potency and pharmacokinetic profiles, for example, 72 (fXa K i 5 0.16 nM, fIIa K i 5 400 nM, trypsin K i 42,500 nM, F 5 38% in dogs) and 73 (fXa K i 5 0.21 nM, fIIa K i 5 300 nM, trypsin K i 41,600 nM, F 5 43% in dogs).…”

Section: Synthetic Direct Fxa Inhibitorsmentioning

confidence: 99%

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Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

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Section: Synthetic Direct Fxa Inhibitorsmentioning

confidence: 99%

“…145 The dimethylaminomethylimidazoyl moiety of 74 further improved the selectivity against trypsin and the oral bioavailability while maintaining potency established in the aminobenzisoxazoles. The cocrystal structure of 74 bound to fXa (PDB code 1Z6E) showed that the aminobenzisoxazole binds to the S1 pocket.…”

Section: Synthetic Direct Fxa Inhibitorsmentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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“…Modification of the DPC423 series has led to additional orally bioavailable FXa inhibitors, including razaxaban (DPC906, BMS-561389, Fig. 1) [4]. In this study we evaluated the efficacy of this potent and selective FXa inhibitor in prevention of arterial thrombosis in a rabbit model of the electrolytic injury-induced carotid artery thrombosis (ECAT) [5] and examined its ex vivo effects on coagulation parameters to confirm its selectivity.…”

Section: Introductionmentioning

confidence: 99%

“…In this study we evaluated the efficacy of this potent and selective FXa inhibitor in prevention of arterial thrombosis in a rabbit model of the electrolytic injury-induced carotid artery thrombosis (ECAT) [5] and examined its ex vivo effects on coagulation parameters to confirm its selectivity. We selected rabbits as the animal model because razaxaban has similar potency in inhibiting human and rabbit FXa (K i = 0.19 nM in human and 0.16 nM in rabbit) [4].…”

Section: Introductionmentioning

confidence: 99%

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

Wong

Crain

Watson

et al. 2007

J Thromb Thrombolysis

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Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial thrombosis. Combination therapy with antiplatelet and anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial thrombosis. Few studies have thoroughly investigated the combined antithrombotic and bleeding effects of these antithrombotic agents. We, therefore, evaluated the antithrombotic and bleeding profiles of dual and triple therapy with razaxaban, a direct factor Xa inhibitor, plus aspirin and/or clopidogrel in rabbit models of electrolytic injury-induced carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6). Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo thrombin activity. Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to ADP, gamma-thrombin or collagen. To identify additive or synergistic antithrombotic effects of the various combination therapies, we purposefully used marginally effective doses of razaxaban at 0.1 mg/kg/h, aspirin at 0.3 mg/kg/h and clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of razaxaban and aspirin or clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual therapy with aspirin and clopidogrel (38 +/- 5% increase in blood flow), addition of razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary, razaxaban was an effective antithrombotic agent in a rabbit model of arterial thrombosis. Low-dose razaxaban was useful in combination with sub-optimal doses of aspirin and/or clopidogrel for the prevention of occlusive arterial thrombosis without excessive bleeding.

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“…Razaxaban (37; Schema 14) war in Phase II der klinischen Entwicklung. [53] Seine Molekülstruktur wurde von dem für Trypsin nicht so selektiven FXa-Inhibitor DPC423 (36) abgeleitet. DPC423 war mit seiner gegenüber einem Benzamidin abgeschwächt basischen Benzylamin-P1-Gruppe oral bioverfügbar.…”

Section: Angewandte Chemieunclassified

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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Discovery of 1-(3‘-Aminobenzisoxazol-5‘-yl)-3-trifluoromethyl-N-[2-fluoro-4- [(2‘-dimethylaminomethyl)imidazol-1-yl]phenyl]-1H-pyrazole-5-carboxyamide Hydrochloride (Razaxaban), a Highly Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor

Cited by 183 publications

References 22 publications

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits

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

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