molecular formula C25H25N5O4 B1684502 Apixaban CAS No. 503612-47-3

Apixaban

Cat. No.: B1684502
CAS No.: 503612-47-3
M. Wt: 459.5 g/mol
InChI Key: QNZCBYKSOIHPEH-UHFFFAOYSA-N
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Description

Apixaban, marketed under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation. It works by directly inhibiting factor Xa, an enzyme crucial for blood clotting . This compound is also used to prevent blood clots following hip or knee replacement surgery and in patients with a history of prior clots .

Mechanism of Action

Target of Action

Apixaban is an oral, direct, and highly selective inhibitor of both free and bound factor Xa (FXa), as well as prothrombinase . Factor Xa is a crucial enzyme in the coagulation cascade, responsible for the conversion of prothrombin to thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin, leading to clot formation .

Mode of Action

This compound acts as a competitive inhibitor of factor Xa . By binding to the active site of factor Xa, it prevents the conversion of prothrombin to thrombin, thereby inhibiting the formation of fibrin clots . This interaction with its targets results in a decrease in thrombin generation and thrombus development .

Biochemical Pathways

This compound affects the coagulation cascade, a series of biochemical reactions that lead to the formation of a fibrin clot. By inhibiting factor Xa, this compound disrupts this cascade, preventing the conversion of prothrombin to thrombin and ultimately the formation of fibrin clots .

Pharmacokinetics

This compound has an absolute oral bioavailability of approximately 50%, meaning about half of the ingested dose reaches systemic circulation . It is rapidly absorbed, with maximum concentration occurring 3–4 hours after oral administration . This compound has a half-life of approximately 12 hours, and its elimination occurs via multiple pathways including metabolism, biliary excretion, and direct intestinal excretion, with approximately 27% of total this compound clearance occurring via renal excretion .

Result of Action

The primary molecular effect of this compound is the inhibition of factor Xa, which leads to a decrease in thrombin generation and thus a reduction in fibrin clot formation . On a cellular level, this results in a reduced propensity for platelet aggregation and clot formation, thereby exerting an anticoagulant effect .

Action Environment

The action of this compound can be influenced by various environmental factors. Furthermore, polymorphisms of CYP3A5 and P-glycoprotein (P-gp) have been suggested as contributing factors to ethnic differences in this compound pharmacokinetics .

Biochemical Analysis

Biochemical Properties

Apixaban plays a crucial role in biochemical reactions by inhibiting blood coagulation factor Xa . This inhibition prevents the conversion of prothrombin to thrombin, thereby reducing the formation of blood clots. This compound interacts with various enzymes, proteins, and other biomolecules involved in the coagulation cascade. Specifically, it binds to the active site of factor Xa, blocking its activity and preventing the downstream activation of thrombin . This interaction is highly selective and potent, making this compound an effective anticoagulant.

Cellular Effects

This compound exerts significant effects on various types of cells and cellular processes. By inhibiting factor Xa, this compound influences cell function, particularly in endothelial cells and platelets. It reduces the activation of platelets and the release of pro-coagulant factors, thereby decreasing the overall pro-thrombotic state . Additionally, this compound affects cell signaling pathways involved in coagulation and inflammation, leading to changes in gene expression and cellular metabolism. These effects contribute to the overall anticoagulant and anti-inflammatory properties of this compound.

Molecular Mechanism

The molecular mechanism of action of this compound involves its binding interactions with factor Xa. This compound binds to the active site of factor Xa, inhibiting its enzymatic activity and preventing the conversion of prothrombin to thrombin . This inhibition is achieved through competitive binding, where this compound competes with the natural substrate of factor Xa for the active site. By blocking the activity of factor Xa, this compound disrupts the coagulation cascade and reduces the formation of blood clots. Additionally, this compound may influence gene expression by modulating the activity of transcription factors involved in coagulation and inflammation.

Temporal Effects in Laboratory Settings

In laboratory settings, the effects of this compound can change over time. This compound is known for its stability and rapid onset of action . Its effects may diminish over time due to degradation and metabolism. Long-term studies have shown that this compound maintains its anticoagulant properties for extended periods, but its efficacy may decrease with prolonged exposure . In vitro and in vivo studies have demonstrated that this compound can have long-term effects on cellular function, including changes in gene expression and cellular metabolism.

Dosage Effects in Animal Models

The effects of this compound vary with different dosages in animal models. At therapeutic doses, this compound effectively inhibits factor Xa and reduces the formation of blood clots . At higher doses, this compound may exhibit toxic or adverse effects, including bleeding complications and impaired wound healing . Threshold effects have been observed, where the anticoagulant activity of this compound increases with increasing doses until a plateau is reached. These findings highlight the importance of careful dosage management to achieve optimal therapeutic outcomes while minimizing adverse effects.

Metabolic Pathways

This compound is involved in various metabolic pathways, including its interaction with enzymes and cofactors. It is primarily metabolized by the liver, where it undergoes oxidative metabolism mediated by cytochrome P450 enzymes, particularly CYP3A4 and CYP3A5 . Additionally, this compound is a substrate for P-glycoprotein, a transporter protein involved in drug efflux. These metabolic pathways influence the pharmacokinetics and bioavailability of this compound, affecting its overall efficacy and safety profile.

Transport and Distribution

This compound is transported and distributed within cells and tissues through various mechanisms. It is absorbed in the gastrointestinal tract and reaches peak plasma concentrations within a few hours . This compound is highly protein-bound, primarily to albumin, which facilitates its distribution throughout the body. It is also transported by P-glycoprotein, which influences its localization and accumulation in different tissues. These transport and distribution mechanisms play a crucial role in determining the pharmacokinetics and therapeutic effects of this compound.

Subcellular Localization

The subcellular localization of this compound is primarily in the cytoplasm and nucleus of cells . It does not require specific targeting signals or post-translational modifications for its activity. This compound’s presence in the cytoplasm allows it to interact with factor Xa and inhibit its activity, while its presence in the nucleus may influence gene expression and cellular metabolism. The subcellular localization of this compound is essential for its anticoagulant and anti-inflammatory effects.

Chemical Reactions Analysis

Scientific Research Applications

Apixaban has a wide range of scientific research applications:

Properties

IUPAC Name

1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI

InChI=1S/C25H25N5O4/c1-34-19-11-9-18(10-12-19)30-23-20(22(27-30)24(26)32)13-15-29(25(23)33)17-7-5-16(6-8-17)28-14-3-2-4-21(28)31/h5-12H,2-4,13-15H2,1H3,(H2,26,32)
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

QNZCBYKSOIHPEH-UHFFFAOYSA-N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Canonical SMILES

COC1=CC=C(C=C1)N2C3=C(CCN(C3=O)C4=CC=C(C=C4)N5CCCCC5=O)C(=N2)C(=O)N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C25H25N5O4
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

DTXSID80436500
Record name Apixaban
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URL https://comptox.epa.gov/dashboard/DTXSID80436500
Description DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight

459.5 g/mol
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Solubility

0.11mg/mL, Aqueous solubility across the physiological pH range is approximately 0.04 mg/L
Record name Apixaban
Source DrugBank
URL https://www.drugbank.ca/drugs/DB06605
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
Record name Apixaban
Source Hazardous Substances Data Bank (HSDB)
URL https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8223
Description The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel.

Mechanism of Action

Apixaban selectively inhibits factor Xa in its free and bound forms, independant of antithrombin III. Apixaban also inhibits prothrominase. These effects prevent the formation of a thrombus.
Record name Apixaban
Source DrugBank
URL https://www.drugbank.ca/drugs/DB06605
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

Color/Form

White to pale-yellow powder

CAS No.

503612-47-3
Record name Apixaban
Source CAS Common Chemistry
URL https://commonchemistry.cas.org/detail?cas_rn=503612-47-3
Description CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society.
Explanation The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
Record name Apixaban
Source DrugBank
URL https://www.drugbank.ca/drugs/DB06605
Description The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
Record name Apixaban
Source EPA DSSTox
URL https://comptox.epa.gov/dashboard/DTXSID80436500
Description DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.
Record name (1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxamide)
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Record name APIXABAN
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Record name Apixaban
Source Hazardous Substances Data Bank (HSDB)
URL https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8223
Description The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel.

Synthesis routes and methods I

Procedure details

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Synthesis routes and methods II

Procedure details

Method B. A solution of 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 ethyl ester (65, 977 mg, 2.0 mmol) in DMF (5 mL) was treated with formamide (901 mg, 0.8 mL, 20 mmol, 10.0 equiv) at room temperature, and the resulting reaction mixture was cooled down to 0–5C before being treated dropwise with a solution of MeONa (864 mg, 0.92 mL, 4.0 mmol, 2.0 equiv) in methanol at 0–5C. The resulting reaction mixture was stirred at 0–5° C. for 30 min before being gradually warmed up to room temperature for an additional 3 h. When HPLC and TLC showed the reaction was complete, the reaction mixture was slowly poured into water (20 mL). The resulting mixture was then stirred at room temperature for 1 h to precipitate the desired product. The solids were collected by filtration, washed with water (2×10 mL) and methyl tert-butyl ether (2×10 mL), dried in vacuo at 40–45° C. for 12 h to afford the crude desired 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 (62, 653 mg, 919 mg theoretical, 71%) as off-whit crystals. This product was found to be identical with the material prepared from method A.
Quantity
0.8 mL
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reactant
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5 mL
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MeONa
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0.92 mL
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reactant
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0 (± 1) mol
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20 mL
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Synthesis routes and methods III

Procedure details

Method A. A suspension of 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 (61, 1.5 g, 3.3 mmol) in EtOAc (20 mL) was treated with triethylamine (TEA, 433 mg, 0.60 mL, 4.3 mmol, 1.3 equiv) at room temperature, and the resulting reaction mixture was treated dropwise with iso-butyl chloroformate (587 mg, 0.55 mL, 4.3 mmol, 1.3 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for an additional 30 min. When TLC and HPLC showed the mixed anhydride formation reaction was complete, the reaction mixture was poured into a cold (0–5° C.) ammonium hydroxide solution (NH4OH, 28% aqueous solution, 25 mL) with good stirring. The resulting mixture was stirred at room temperature for an additional 4 h. The solids were collected by filtration, washed with a mixture of methanol and water (1:1 v/v, 2×20 mL), and dried in vacuo at 40–45° C. for 12 h to afford the crude desired 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 (62, 1.06 g, 1.52 g theoretical, 70%) as off-white crystals. For 62, CIMS m/z 460 (M++H, C25H25N5O4).
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Quantity
20 mL
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0.6 mL
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0.55 mL
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[Compound]
Name
anhydride
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0 (± 1) mol
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25 mL
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Retrosynthesis Analysis

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Strategy Settings

Precursor scoring Relevance Heuristic
Min. plausibility 0.01
Model Template_relevance
Template Set Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis
Top-N result to add to graph 6

Feasible Synthetic Routes

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