Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1<i>H</i>-pyrazolo[3,4-<i>c</i>]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

Pinto, Donald; Orwat, Michael J.; Koch, Stephanie; Rossi, Karen A.; Alexander, Richard; Smallwood, Angela; Wong, Pancras C.; Rendina, Alan R.; Luettgen, Joseph M.; Knabb, Robert M.; He, Kan; Xin, Baomin; Wexler, Ruth R.; Lam, Patrick Y.S.

doi:10.1021/jm070245n

Cited by 368 publications

(176 citation statements)

References 39 publications

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“…Apixaban is a potent, oral, reversible, direct factor (F) Xa inhibitor with greater than 30 000-fold selectivity over other coagulation proteases [6,7]. By inhibiting FXa, apixaban has the potential to reduce the generation of thrombin and thereby attenuate its thrombotic effects.…”

Section: Introductionmentioning

confidence: 99%

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

Wong

Watson

Crain

2008

Journal of Thrombosis and Haemostasis

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To cite this article: Wong PC, Watson CA, Crain EJ. Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008; 6: 1736-41.Summary. Background: Optimal treatment of arterial thrombosis may include a combination of antiplatelet and anticoagulant drugs. We evaluated apixaban, a direct and highly selective factor Xa inhibitor, in combination with clinically relevant doses of aspirin and/or clopidogrel for prevention of arterial thrombosis in rabbits. Methods: Studies were conducted in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time (BT). Apixaban 0.04 and 0.3 mg kg )1 h )1 or aspirin 1 mg kg )1 h )1 was infused intravenous (i.v.) continuously from 1 h before artery injury or cuticle bleed until the end of the experiment. Clopidogrel at 3 mg kgwas dosed orally once daily for three days, with the last dose given 2 h before injury. Results: Control thrombus weight and BT averaged 8.6 ± 0.9 mg and 181 ± 12 s, respectively (n = 6 per group). Effective doses of apixaban that reduced thrombus weight by 20 and 50% (ED 20 and ED 50 ) were 0.04 and 0.3 mg kg )1 h )1 i.v., respectively. Addition of aspirin to apixaban ED 20 and ED 50 significantly reduced the thrombus weight from 7.4 ± 0.5 to 5.3 ± 0.3 and 3.6 ± 0.3 mg, respectively, with no significant increases in BT (190 ± 7 s vs.181 ± 9 and 225 ± 11 s, respectively). Addition of aspirin and apixaban (ED 20 dose) to clopidogrel produced a further significant reduction in thrombus weight from 5.3 ± 0.3 to 0.7 ± 0.1 mg. This combination of clopidogrel and aspirin with apixaban (ED 20 dose) produced a significant but moderate BT increase of 2.1 times control. Conclusions: The combination of apixaban and aspirin or apixaban, aspirin and clopidogrel can reduce formation of occlusive arterial thrombosis without excessive increases in BT in rabbits.

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Section: Introductionmentioning

confidence: 99%

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

Wong

Watson

Crain

2008

Journal of Thrombosis and Haemostasis

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“…It is a new generation of oral anticoagulant drug that selectively inhibits coagulation factor Xa. [1]. It is used in thromboprophylaxis in patients following total knee replacement surgery with a desired efficacy and safety profile [2].…”

Section: Apixaban Is Chemically 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxomentioning

confidence: 99%

Development and Validation of HPTLC Method for Determination Apixaban in Bulk and Tablets

Jain

Nikam

2017

Int J App Pharm

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Objective: To develop a simple and sensitive, high-performance thin layer chromatographic (HPTLC) method for the quantitative estimation of apixaban in bulk and tablets.Methods: Sample of apixaban was applied on silica gel 60 F254 TLC plates under pure nitrogen stream by linomat TLC applicator. Separation was carried out by using toluene, methanol and diethylamine as a mobile phase in a ratio of 16:3:1 v/v/v. Developed TLC plates were scanned by camag TLC scanner and detection was carried out at 288 nm.Results: Rf value of apixaban was found to be 0.4. The linearity was found from 50 to 350 ng/spot. The mean percentage recovery was found to be 85.66with % RSD of 0.79. Conclusion:The present study represents first HPTLC method that deals with the estimation of apixaban. Validation results indicated that the developed method is simple, rapid, accurate, specific, sensitive and precise. The developed method was validated as per ICH Q2 (R1) guideline by studying various validation parameters like accuracy, precision, specificity, assay, LOD and LOQ. It can be concluded that the method can be used in routine analysis of apixaban in tablet dosage form.

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“…Sharma et al conducted a meta-analysis of 19 RCTs regarding 4 DOACs (rivaroxaban, apixaban, edoxaban, and dabigatran) and reported that major bleeding risks were comparable between rivaroxaban and warfarin (HR, 0.81; 95% CI, 0.67-0.98), but significantly lower for apixaban (HR, 0.63; 95% CI, 0.51-0.77) and edoxaban 60 mg once daily (HR, 0.81; 95% CI, 0.67-0.98) regardless of age 6 ; Nielsen et al analyzed the data of 61 678 patients with nonvalvular AF that were identified from 3 Danish nationwide databases and also reported that rivaroxaban had a risk of major bleeding comparable to that of warfarin (HR, 1.06; 95% CI, 0.91-1.23), whereas that of apixaban was significantly lower than the risk associated with warfarin (HR, 0.61; 95% CI, 0.49-0.75). 7 Given the same mechanism of action of the 3 FXa inhibitors, [8][9][10][11] we hypothesized that these variabilities would be attributed to the fact that their current doses are not fully optimized from the perspective of the risk-benefit balance.…”

Section: Introductionmentioning

confidence: 99%

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

et al. 2018

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Key Points• Simulations suggested that the dose reduction of rivaroxaban would decrease fatal events associated with major bleeding.• Dose optimization of FXa inhibitors might further enhance their therapeutic benefit.The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta-analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding.

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Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa

Cited by 368 publications

References 39 publications

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits

Development and Validation of HPTLC Method for Determination Apixaban in Bulk and Tablets

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

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