molecular formula C25H25N7O3 B194492 Dabigatran CAS No. 211914-51-1

Dabigatran

Cat. No.: B194492
CAS No.: 211914-51-1
M. Wt: 471.5 g/mol
InChI Key: YBSJFWOBGCMAKL-UHFFFAOYSA-N
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Mechanism of Action

Target of Action

Dabigatran is a direct thrombin inhibitor . Thrombin, a plasma serine protease, plays a central role in coagulation and hemostasis . It catalyzes the conversion of fibrinogen to fibrin during the coagulation cascade . Therefore, thrombin is the primary target of this compound .

Mode of Action

This compound reversibly binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors . It inhibits both free and clot-bound thrombin . This inhibition is rapid and reversible . This compound has been shown to be a potent, competitive, and reversible inhibitor of thrombin, inhibiting both thrombin activity and generation .

Biochemical Pathways

By inhibiting thrombin, this compound prevents the development of a thrombus . Thrombin catalyzes the conversion of factors V, VIII, and XI to their activated forms and the conversion of fibrinogen to fibrin . Thrombin also activates transmembrane G-protein-coupled protease-activated receptors on the platelet cell membrane. Downstream signaling results in conformational change, allowing platelet aggregation and release of more coagulation factors and generation of more thrombin . By inhibiting thrombin, this compound disrupts these pathways and acts as an anticoagulant .

Pharmacokinetics

This compound etexilate, the prodrug of this compound, is rapidly absorbed and converted to its active form, this compound . The bioavailability of this compound after oral administration of this compound etexilate is 3-7% . Peak plasma concentrations of this compound are reached approximately 2 hours after oral administration . The elimination half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug .

Result of Action

The molecular and cellular effects of this compound’s action include the prevention of thrombus formation by inhibiting thrombin . This results in anticoagulation, reducing the risk of venous thromboembolic events . At the cellular level, this compound-fed mice exhibited reduced atherosclerotic lesion size along with enhanced plaque stability, improved endothelial function, and reduced oxidative stress .

Action Environment

Environmental factors such as the presence of active cancer can influence the efficacy and safety of this compound . Furthermore, this compound oral bioavailability requires an acidic environment, which increases the burden of the gastrointestinal (GI) tract and the risk of GI bleeding . Therefore, the patient’s health status and the physiological environment can significantly influence this compound’s action, efficacy, and stability.

Biochemical Analysis

Biochemical Properties

Dabigatran is a potent, competitive, and reversible inhibitor of thrombin, inhibiting both thrombin activity and generation . It interacts with thrombin, a plasma serine protease that plays a central role in coagulation and hemostasis . This compound binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors .

Cellular Effects

This compound has been shown to suppress the activation of astrocytes, cells that play a key role in the central nervous system . The underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs) .

Molecular Mechanism

This compound exerts its effects at the molecular level by directly inhibiting the conversion of fibrinogen to fibrin by thrombin, impairing the clotting process and acting as an anticoagulant . It binds reversibly to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors .

Temporal Effects in Laboratory Settings

This compound has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring . Peak plasma concentrations of this compound are reached approximately 2 hours after oral administration . The elimination half-life is 12 to 14 hours, with clearance predominantly occurring via renal excretion of unchanged drug .

Dosage Effects in Animal Models

In animal models, this compound has been shown to reduce atherosclerotic lesion size along with enhanced plaque stability, improved endothelial function, and reduced oxidative stress . In a study using sheep as a model, this compound was found to provide acceptable anticoagulation similar to heparin to prevent thrombosis .

Metabolic Pathways

This compound is metabolized primarily by esterases . It is not metabolized by cytochrome P450 isoenzymes . The predominant metabolic reaction is esterase-mediated hydrolysis of this compound etexilate to this compound .

Transport and Distribution

This compound etexilate is a substrate of esterases and P-glycoprotein (P-gp) . After oral administration, it is rapidly absorbed and converted to its active form, this compound .

Subcellular Localization

The subcellular localization of this compound is not explicitly mentioned in the literature. Given its role as a direct thrombin inhibitor, it is likely to be found wherever thrombin is present in the cell. Thrombin is a serine protease that plays a central role in coagulation and hemostasis , suggesting that this compound would be localized in areas of the cell involved in these processes.

Properties

IUPAC Name

3-[[2-[(4-carbamimidoylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoic acid
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI

InChI=1S/C25H25N7O3/c1-31-20-10-7-17(25(35)32(13-11-23(33)34)21-4-2-3-12-28-21)14-19(20)30-22(31)15-29-18-8-5-16(6-9-18)24(26)27/h2-10,12,14,29H,11,13,15H2,1H3,(H3,26,27)(H,33,34)
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

InChI Key

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

Canonical SMILES

CN1C2=C(C=C(C=C2)C(=O)N(CCC(=O)O)C3=CC=CC=N3)N=C1CNC4=CC=C(C=C4)C(=N)N
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

Molecular Formula

C25H25N7O3
Source PubChem
URL https://pubchem.ncbi.nlm.nih.gov
Description Data deposited in or computed by PubChem

DSSTOX Substance ID

DTXSID50175419
Record name Dabigatran
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Molecular Weight

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

Mechanism of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties., ... To evaluate the profibrinolytic effect of dabigatran, a new, direct thrombin inhibitor, using different in vitro models. The resistance of tissue factor-induced plasma clots to fibrinolysis by exogenous tissue-type plasminogen activator (t-PA) (turbidimetric method) was reduced by dabigatran in a concentration-dependent manner, with > or = 50% shortening of lysis time at clinically relevant concentrations (1-2 um). A similar effect was observed in the presence of low (0.1 and 1 nm) but not high (10 nm) concentrations of thrombomodulin. Acceleration of clot lysis by dabigatran was associated with a reduction in TAFI activation and thrombin generation, and was largely, although not completely, negated by an inhibitor of activated TAFI, potato tuber carboxypeptidase inhibitor. The assessment of the viscoelastic properties of clots showed that those generated in the presence of dabigatran were more permeable, were less rigid, and consisted of thicker fibers. The impact of these physical changes on fibrinolysis was investigated using a model under flow conditions, which demonstrated that dabigatran made the clots markedly more susceptible to flowing t-PA, by a mechanism that was largely TAFI-independent. Dabigatran, at clinically relevant concentrations, enhances the susceptibility of plasma clots to t-PA-induced lysis by reducing TAFI activation and by altering the clot structure. These mechanisms might contribute to the antithrombotic activity of the drug.
Record name Dabigatran
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Color/Form

White crystals

CAS No.

211914-51-1
Record name Dabigatran
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Record name Dabigatran
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Record name DABIGATRAN
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Melting Point

276-277 °C
Record name Dabigatran
Source Hazardous Substances Data Bank (HSDB)
URL https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8062
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

Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 91% of theory, C25H25N7O3 (471.5); EKA mass spectrum: (M+H)+=472; (M+H+Na)++=247.6; (M+2H)++=236.7; (M+2Na)++=258.6.
Quantity
0 (± 1) mol
Type
reactant
Reaction Step One
[Compound]
Name
C25H25N7O3
Quantity
0 (± 1) mol
Type
reactant
Reaction Step Two

Synthesis routes and methods II

Procedure details

Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.

Retrosynthesis Analysis

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Strategy Settings

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Min. plausibility 0.01
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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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