Dabigatran
Vue d'ensemble
Description
Dabigatran est un inhibiteur direct de la thrombine utilisé comme anticoagulant pour prévenir et traiter les caillots sanguins et pour réduire le risque d'AVC chez les patients atteints de fibrillation auriculaire . Il est commercialisé sous le nom de marque Pradaxa, entre autres . This compound est particulièrement utilisé pour prévenir la formation de caillots sanguins après une chirurgie de remplacement de la hanche ou du genou et chez les patients ayant des antécédents de caillots .
Mécanisme D'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.
Applications De Recherche Scientifique
Dabigatran has a wide range of scientific research applications. In medicine, it is used to prevent thromboembolic events and stroke in patients with atrial fibrillation . It is also used in the treatment of deep vein thrombosis and pulmonary embolism . In biological research, this compound is used to study the coagulation cascade and thrombin inhibition . Additionally, it has applications in the pharmaceutical industry for the development of new anticoagulant therapies .
Analyse Biochimique
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.
Méthodes De Préparation
La synthèse du dabigatran implique plusieurs étapes. Une méthode comprend la condensation de la 4-aminobenzamidine avec le chloroformiate d'hexyle pour obtenir du N-n-hexyl-4-aminobenzamidine-carbamate . Cet intermédiaire est ensuite encore réagi avec R1CH2COOH pour produire de l'acide 2-(4-(N’-formiate d'hexyle)amidino)aniline)acétique . Les méthodes de production industrielle impliquent souvent l'utilisation d'intermédiaires cristallins pour garantir la pureté et le rendement .
Analyse Des Réactions Chimiques
Dabigatran subit diverses réactions chimiques, notamment la substitution nucléophile et l'hydrolyse. Par exemple, la substitution nucléophile de l'amidine par du carbonate de n-hexyl-4-nitrophényle entraîne la formation de la base this compound . Les réactifs couramment utilisés dans ces réactions comprennent le chloroformiate d'hexyle et l'acide méthanesulfonique . Le principal produit formé par ces réactions est le mésylate de this compound etexilate .
Applications de recherche scientifique
This compound a un large éventail d'applications de recherche scientifique. En médecine, il est utilisé pour prévenir les événements thromboemboliques et les accidents vasculaires cérébraux chez les patients atteints de fibrillation auriculaire . Il est également utilisé dans le traitement de la thrombose veineuse profonde et de l'embolie pulmonaire . En recherche biologique, le this compound est utilisé pour étudier la cascade de coagulation et l'inhibition de la thrombine . De plus, il a des applications dans l'industrie pharmaceutique pour le développement de nouvelles thérapies anticoagulantes .
Mécanisme d'action
This compound agit en inhibant la thrombine, une sérine protéase qui joue un rôle clé dans la cascade de coagulation . En se liant à la thrombine, le this compound empêche la conversion du fibrinogène en fibrine, inhibant ainsi la formation de caillots . Ce mécanisme le rend efficace pour réduire le risque d'AVC et d'autres événements thromboemboliques .
Comparaison Avec Des Composés Similaires
Dabigatran est souvent comparé à d'autres anticoagulants tels que l'apixaban, le rivaroxaban et l'edoxaban . Contrairement à la warfarine, le this compound ne nécessite pas de surveillance régulière du sang et présente moins d'interactions médicamenteuses . Par rapport au rivaroxaban et à l'edoxaban, le this compound présente un risque plus faible de saignement majeur . L'apixaban, cependant, s'est avéré avoir un profil de sécurité légèrement plus favorable que celui du this compound .
Des composés similaires comprennent :
- Apixaban
- Rivaroxaban
- Edoxaban
- Warfarine
Ces composés, comme le this compound, sont utilisés comme anticoagulants, mais diffèrent par leur mécanisme d'action, leurs effets secondaires et leurs exigences de surveillance .
Propriétés
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. | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
One-Step Synthesis Focus: Specifically designed for one-step synthesis, it provides concise and direct routes for your target compounds, streamlining the synthesis process.
Accurate Predictions: Utilizing the extensive PISTACHIO, BKMS_METABOLIC, PISTACHIO_RINGBREAKER, REAXYS, REAXYS_BIOCATALYSIS database, our tool offers high-accuracy predictions, reflecting the latest in chemical research and data.
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
Avertissement et informations sur les produits de recherche in vitro
Veuillez noter que tous les articles et informations sur les produits présentés sur BenchChem sont destinés uniquement à des fins informatives. Les produits disponibles à l'achat sur BenchChem sont spécifiquement conçus pour des études in vitro, qui sont réalisées en dehors des organismes vivants. Les études in vitro, dérivées du terme latin "in verre", impliquent des expériences réalisées dans des environnements de laboratoire contrôlés à l'aide de cellules ou de tissus. Il est important de noter que ces produits ne sont pas classés comme médicaments et n'ont pas reçu l'approbation de la FDA pour la prévention, le traitement ou la guérison de toute condition médicale, affection ou maladie. Nous devons souligner que toute forme d'introduction corporelle de ces produits chez les humains ou les animaux est strictement interdite par la loi. Il est essentiel de respecter ces directives pour assurer la conformité aux normes légales et éthiques en matière de recherche et d'expérimentation.
![(8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 3-hydroxy-2-phenylpropanoate;sulfuric acid;dihydrate](/img/structure/B194442.png)
