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Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor.

Wong PC, Pinto DJ, Zhang D - J. Thromb. Thrombolysis (2011)

Bottom Line: With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases.Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation.Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. pancras.wong@bms.com

ABSTRACT
Apixaban (BMS-562247; 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), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 μM⁻¹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.

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Related in: MedlinePlus

X-ray structure of apixaban bound to factor Xa
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Fig2: X-ray structure of apixaban bound to factor Xa

Mentions: Development of razaxaban was quickly followed by the identification of a novel bicyclic tetrahydropyrazolo-pyridinone analog 7 (BMS-740808, FXa Ki = 0.03 nM) [34]. The evolution of the bicyclic pyrazole template allowed for the incorporation of a diverse set of P1 groups, the most important of which was the p-methoxyphenyl analog 8 (Ki = 0.14 nM) [13]. Compound 8 retained potent FXa affinity and good anticoagulant activity in vitro, was efficacious in in vivo rabbit antithrombotic models and showed high oral bioavailability in dogs. A significant breakthrough was subsequently achieved, via the incorporation of a pendent P4 lactam group and a carboxamido pyrazole moiety, that led to the discovery of 9 (BMS-562247, FXa Ki = 0.08 nM) [13], a highly potent and selective FXa inhibitor with good efficacy in various animal models of thrombosis. Importantly, compound 9 also showed an excellent pharmacokinetic profile in dogs, with low clearance, low volume of distribution and high oral bioavailability [13]. The superior pre-clinical profile demonstrated by 9 enabled its rapid progression into clinical development as apixaban [15]. Figure 2 illustrates the X-ray structure of apixaban bound to FXa and shows the p-methoxyphenyl P1 deeply inserted into the S1 pocket, with the aryllactam P4 moiety neatly stacked in the hydrophobic S4 pocket.Fig. 2


Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor.

Wong PC, Pinto DJ, Zhang D - J. Thromb. Thrombolysis (2011)

X-ray structure of apixaban bound to factor Xa
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3090580&req=5

Fig2: X-ray structure of apixaban bound to factor Xa
Mentions: Development of razaxaban was quickly followed by the identification of a novel bicyclic tetrahydropyrazolo-pyridinone analog 7 (BMS-740808, FXa Ki = 0.03 nM) [34]. The evolution of the bicyclic pyrazole template allowed for the incorporation of a diverse set of P1 groups, the most important of which was the p-methoxyphenyl analog 8 (Ki = 0.14 nM) [13]. Compound 8 retained potent FXa affinity and good anticoagulant activity in vitro, was efficacious in in vivo rabbit antithrombotic models and showed high oral bioavailability in dogs. A significant breakthrough was subsequently achieved, via the incorporation of a pendent P4 lactam group and a carboxamido pyrazole moiety, that led to the discovery of 9 (BMS-562247, FXa Ki = 0.08 nM) [13], a highly potent and selective FXa inhibitor with good efficacy in various animal models of thrombosis. Importantly, compound 9 also showed an excellent pharmacokinetic profile in dogs, with low clearance, low volume of distribution and high oral bioavailability [13]. The superior pre-clinical profile demonstrated by 9 enabled its rapid progression into clinical development as apixaban [15]. Figure 2 illustrates the X-ray structure of apixaban bound to FXa and shows the p-methoxyphenyl P1 deeply inserted into the S1 pocket, with the aryllactam P4 moiety neatly stacked in the hydrophobic S4 pocket.Fig. 2

Bottom Line: With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases.Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation.Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Biology, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. pancras.wong@bms.com

ABSTRACT
Apixaban (BMS-562247; 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), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 μM⁻¹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.

Show MeSH
Related in: MedlinePlus