Apixaban

Apixaban Basic information
Indications and Usage Mechanisms of Action Clinical Research Drug Interactions Warnings and Precautions
Product Name:Apixaban
Synonyms:Apixaban;Apixaban, BMS 562247-01;BMS 562247-01;1-(4-Methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid aMide;1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4, 5-dihydropyrazolo[3,4-c]pyridine-3-carboxaMide;Nilotinib and its interMediate;Apixaban ,ELIQUIS;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
CAS:503612-47-3
MF:C25H25N5O4
MW:459.5
EINECS:639-684-6
Product Categories:Inhibitors;Inhibitor;API;503612-47-3
Mol File:503612-47-3.mol
Apixaban Structure
Apixaban Chemical Properties
Melting point 235-238°C
Boiling point 770.5±60.0 °C(Predicted)
density 1.42
storage temp. Refrigerator
solubility DMSO (Slightly, Heated), Methanol (Slightly)
pka15.01±0.20(Predicted)
form Solid
color White to Off-White
InChIKeyQNZCBYKSOIHPEH-UHFFFAOYSA-N
SMILESC1(=O)N(C2=CC=C(N3CCCCC3=O)C=C2)CCC2C(C(N)=O)=NN(C3=CC=C(OC)C=C3)C1=2
Safety Information
Hazardous Substances Data503612-47-3(Hazardous Substances Data)
MSDS Information
Apixaban Usage And Synthesis
Indications and UsageApixaban is a new form of oral anticoagulant drug developed by Bristol Myers Squibb and Pfizer. It is a new form of oral Xa factor inhibitor, and its commercial name is Eliquis. Apixaban is used to treat adult patients undergoing elective hip or knee replacement surgery to prevent venous thromboembolism (VTE)
Mechanisms of ActionApixaban is an oral selective activated Xa factor inhibitor and can prevent thrombin generation and thrombosis.
Clinical ResearchApixaban is the third new oral anticoagulant to go on sale, following dabigatran and rivaroxaban, and it has already been approved in Europe for preventing venous thromboembolism in patients undergoing elective hip or knee replacement surgery. Out of these three oral anticoagulants approved in Europe, compared to the current standard preventative treatment against venous thromboembolism, enoxaparin, rivaroxaban excelled in the record experiment, and apixaban excelled in the advance experiment. Rivaroxaban’s curative effects were slightly superior, but it caused more severe bleeding than apixaban. Researchers attributed these differences to medication time, as rivaroxaban was taken 6-8 hours after surgery in the record experiment, while apixaban was used 18 hours after surgery in the advance experiment. These drugs have better curative effect when used closer to time of surgery, but also have an increased bleeding risk. Clinical research showed that compared to a daily subdermal injection of 40mg enoxaparin, 2 oral 2.5mg dosages of apixaban had better preventative effects against venous thromboembolism following hip or knee replacement surgery and did not increase bleeding risk.
Drug Interactions1.A double inhibitor of strong CYP3A4 and P-gp increases apixaban’s blood levels: decrease Eliquis dosage to 2.5mg or avoid simultaneous usage.
2.A inductor of strong CYP3A4 and P-gp can decrease apixaban’s blood levels: avoid simultaneous usage.
Warnings and Precautions
  • Breastfeeding mothers should stop usage or stop breastfeeding.
  • Use during pregnancy is not advised.
  • Use while experiencing severe liver damage is not advised.
DescriptionApixaban is an orally bioavailable, selective inhibitor of both free and prothrombinase-bound factor Xa (Kis = 0.8 nM). In vivo, apixaban has antithrombotic effects in a rabbit model of venous thrombosis. Apixaban (357.5 mg) also prevents thrombus formation without inducing adverse bleeding events in a porcine model of aortic heterotopic valve replacement. Formulations containing apixaban have been used to prevent blood clot formation in patients with atrial fibrillation.
DescriptionEliquis (apixaban), a direct inhibitor of factor Xa (FXa), was approved by the European Commission on May 18, 2011 for prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. The discovery of apixaban was the culmination of a succession of novel and innovative medicinal chemistry discoveries starting with the identification of nonpeptide leads, rational drug design using computer-aided and X-ray crystallographic information, and the building of drug-like properties through the systematic replacement of basic groups with neutral moieties. Apixaban arose from modifications to razaxaban by constraining a pyrazole amide to form a bicyclic pyrazolo-pyridinone scaffold. Optimization of the P1 group resulted in the identification of the nonbasic methoxy phenyl group, while a P4 piperidinone improved the balance of potency and pharmacokinetics with low Vdss. The synthesis of apixaban begins with the generation of a hydrazone of 4-methoxyaniline which is then used in a 3+2 cycloaddition with a dihydropiperidinone to form a bicyclic pyrazolo-pyridinone scaffold. The distal piperidinone group is installed using an Ullmann coupling reaction followed by aminolysis of an ethyl ester on the pyrazole ring to complete the synthesis of apixaban.
OriginatorBristol Myers Squibb Company (United States)
UsesApixaban is a highly selective, reversible inhibitor of Factor Xa with Ki of 0.08 nM and 0.17 nM in human and rabbit, respectively.
DefinitionChEBI: A pyrazolopyridine that is 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide substituted at position 1 by a 4-methoxyphenyl group and at position 6 by a 4-(2-oxopiperidin-1-yl)phenyl group. It is used for the prevention and treatment of thromboembolic diseases.
Brand nameEliquis
Clinical UseApixaban is an oral anticoagulant with highly selective inhibition of factor Xa. It was approved by the European Medicines Agency (EMA) for the treatment of venous thromboembolic events and first marketed in Germany under the brand name Eliquis in June 2011. Apixaban was co-developed by Bristol-Myers Squibb and Pfizer and represents the first approved drug for this indication since warfarin over 50 years ago.
SynthesisAlthough several convenient preparations of apixaban (BMS-562247) have been reported, the most likely process-scale route is described in the scheme. The starting material 4-iodoaniline (14) was acylated with 5-bromovaleryl chloride (15) and triethylamine followed by cyclization under basic conditions to give lactam 16 in 49% yield. Intermediate 16 was then reacted with phosphorus pentachloride to provide the a,a-dichlorinated lactam 17 in 87% yield.30 This dichloride was reacted with excess morpholine to affect an alkylation¨Celimination sequence to afford enaminolactam 18 in 86% yield. N-Arylation of this iodide with valerolactam 19 using a copper (I) catalyst resulted in a 77% yield of the desired p-bispiperidone 20. Interestingly, sequential exposure of 20 to a nitrile imine generated from the treatment of ethyl 2-chloro-2-(2,4-methoxyphenyl)-hydrazono) acetate 21 with base resulted in a [3+2] dipolarcycloadditon reaction. Upon acidification with 4 N HCl, pyrazole 22 was furnished in 67% over two steps. Conversion of the ester within 22 to the corresponding amide was achieved via a mixture of formamide and sodium methoxide to give apixaban (III) in 71% yield. It is important to note that intermediate 21 was prepared from commercially available 4-methoxyaniline (23) by sequential diazotization and condensation with ethyl 2-chloroacetoacetate (24).

Synthesis_503612-47-3

in vitroapixabanhas exhibited a high degree of potency, selectivity, and efficacy on factor xa with ki of 0.08 nm and 0.17 nm for human factor xa and rabbit factor xa, respectively [1]. apixaban prolonged the clotting times of normal human plasma with the concentrations (ec2x) of 3.6, 0.37, 7.4 and 0.4 μm, which are required respectively to double the prothrombin time (pt), modified prothrombin time (mpt), activated partial thromboplastin time (aptt) and heptest. besides, apixaban showed the highest potency in human and rabbit plasma, but less potency in rat and dog plasma in both the pt and aptt assays [3].
in vivoapixaban exihibited the excellent pharmacokinetics with very low clearance (cl: 0.02 l kg-1h-1), and low volume of distribution (vdss: 0.2 l/kg) in the dog. besides, apixaban also showed a moderate half-life with t1/2 of 5.8 hours and good oral bioavailability (f: 58%) [1]. in the arteriovenous-shunt thrombosis (avst), venous thrombosis (vt) and electrically mediated carotid arterial thrombosis (ecat) rabbit models, apixaban produced antithrombotic effects with ec50 of 270 nm, 110 nm and 70 nm in a dose-dependent manner[3]. apixaban significantly inhibited factor xa activity with an ic50 of 0.22 μm in rabbit ex vivo[4]. in chimpanzee, apixaban also showed small volume of distribution (vdss: 0.17 l kg-1), low systemic clearance (cl: 0.018 l kg-1h-1), and good oral bioavailability (f: 59%) [5].
Drug interactionsPotentially hazardous interactions with other drugs
Analgesics: increased risk of haemorrhage with IV diclofenac and ketorolac - avoid.
Antibacterials: avoid with clarithromycin and telithromycin; concentration possibly reduced by rifampicin - avoid if treating DVT/PE.
Anticoagulants: increased risk of haemorrhage with other anticoagulants - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid if treating DVT/PE.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone - avoid if treating DVT/ PE with carbamazepine.
Antifungals: concentration increased by ketoconazole - avoid; avoid with itraconazole, posaconazole and voriconazole.
Antivirals: avoid with atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir, telaprevir and tipranavir.
Cobicistat: avoid concomitant use.







MetabolismApixaban is metabolised in the liver mainly via the P450 cytochromes CYP3A4 and CYP3A5.
Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. There are also additional contributions from biliary and direct intestinal excretion.
Referenceshttps://en.wikipedia.org/wiki/Apixaban
https://www.drugbank.ca/drugs/DB06605
Apixaban Preparation Products And Raw materials
Apixaban IMpurity( 3-Chloro-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one Ethyl (2Z)-chloro[(4-methoxyphenyl)hydrazono]ethanoate Dabigatran 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one Edoxaban (tosylate Monohydrate) Apixaban IMpurity(BMS-591329-01) 1,3-bis(4-bromophenyl)propan-2-one Apixaban IMpurity 5 (BMS-591329-01) ethyl 6-(4-(5-chloropentanaMido)phenyl)-1-(4-Methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate Apixaban Related Compound 4 Butanoic acid, 2-[(4-hydroxyphenyl)hydrazono]-3-oxo-, ethyl ester Apixaban Impurity 34 ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate Apixaban-13C-D3 Apixaban Impurity 15 Apixaban Impurity 30 Apixaban Impurity 37

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