Dabigatran
Descripción general
Descripción
El dabigatrán es un inhibidor directo de la trombina que se utiliza como anticoagulante para prevenir y tratar los coágulos sanguíneos y para reducir el riesgo de accidente cerebrovascular en pacientes con fibrilación auricular . Se comercializa bajo el nombre comercial Pradaxa, entre otros . El dabigatrán se utiliza particularmente para prevenir los coágulos sanguíneos después de la cirugía de reemplazo de cadera o rodilla y en pacientes con antecedentes de coágulos previos .
Mecanismo De Acción
El dabigatrán funciona inhibiendo la trombina, una serina proteasa que juega un papel clave en la cascada de coagulación . Al unirse a la trombina, el dabigatrán evita la conversión de fibrinógeno en fibrina, inhibiendo así la formación de coágulos . Este mecanismo lo hace eficaz para reducir el riesgo de accidente cerebrovascular y otros eventos tromboembólicos .
Aplicaciones Científicas De Investigación
El dabigatrán tiene una amplia gama de aplicaciones de investigación científica. En medicina, se utiliza para prevenir eventos tromboembólicos y accidentes cerebrovasculares en pacientes con fibrilación auricular . También se utiliza en el tratamiento de la trombosis venosa profunda y la embolia pulmonar . En la investigación biológica, el dabigatrán se utiliza para estudiar la cascada de coagulación y la inhibición de la trombina . Además, tiene aplicaciones en la industria farmacéutica para el desarrollo de nuevas terapias anticoagulantes .
Análisis Bioquímico
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.
Métodos De Preparación
La síntesis de dabigatrán implica varios pasos. Un método incluye la condensación de 4-aminobenzamida con cloroformiato de hexilo para obtener N-n-hexil-4-aminobenzamida-carbamato . Este intermedio se hace reaccionar posteriormente con R1CH2COOH para producir ácido 2-(4-(N’-formiato de hexilo)amidino)anilina)acético . Los métodos de producción industrial a menudo implican el uso de intermedios cristalinos para garantizar la pureza y el rendimiento .
Análisis De Reacciones Químicas
El dabigatrán sufre varias reacciones químicas, incluida la sustitución nucleofílica y la hidrólisis. Por ejemplo, la sustitución nucleofílica de la amidina con carbonato de n-hexil-4-nitrofenilo da como resultado la formación de la base de dabigatrán . Los reactivos comunes utilizados en estas reacciones incluyen cloroformiato de hexilo y ácido metanosulfónico . El producto principal formado a partir de estas reacciones es el mesilato de dabigatrán etexilato .
Comparación Con Compuestos Similares
El dabigatrán se compara a menudo con otros anticoagulantes como apixaban, rivaroxaban y edoxaban . A diferencia de la warfarina, el dabigatrán no requiere un control regular de la sangre y tiene menos interacciones medicamentosas . En comparación con rivaroxaban y edoxaban, el dabigatrán tiene un menor riesgo de hemorragia mayor . Sin embargo, se ha encontrado que el apixaban tiene un perfil de seguridad ligeramente más favorable en comparación con el dabigatrán .
Compuestos similares incluyen:
- Apixaban
- Rivaroxaban
- Edoxaban
- Warfarina
Estos compuestos, como el dabigatrán, se utilizan como anticoagulantes, pero difieren en sus mecanismos de acción, efectos secundarios y requisitos de control .
Propiedades
IUPAC Name |
3-[[2-[(4-carbamimidoylanilino)methyl]-1-methylbenzimidazole-5-carbonyl]-pyridin-2-ylamino]propanoic acid |
Source
|
|---|---|---|
| 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
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
YBSJFWOBGCMAKL-UHFFFAOYSA-N |
Source
|
| 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
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C25H25N7O3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID50175419 |
Source
|
| Record name | Dabigatran | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID50175419 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
471.5 g/mol |
Source
|
| 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. |
Source
|
| 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. | |
Color/Form |
White crystals | |
CAS No. |
211914-51-1 |
Source
|
| Record name | Dabigatran | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=211914-51-1 | |
| 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 | Dabigatran [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0211914511 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Dabigatran | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB14726 | |
| 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 | Dabigatran | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID50175419 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Dabigatran | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | DABIGATRAN | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/I0VM4M70GC | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| 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. | |
Melting Point |
276-277 °C |
Source
|
| 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. | |
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Retrosynthesis Analysis
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