Dabigatran
Übersicht
Beschreibung
Dabigatran ist ein direkter Thrombininhibitor, der als Antikoagulans zur Vorbeugung und Behandlung von Blutgerinnseln und zur Reduzierung des Schlaganfallrisikos bei Patienten mit Vorhofflimmern eingesetzt wird . Es wird unter anderem unter dem Markennamen Pradaxa vermarktet . This compound wird insbesondere zur Vorbeugung von Blutgerinnseln nach Hüft- oder Kniegelenkersatz und bei Patienten mit Vorerkrankungen eingesetzt .
Wirkmechanismus
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.
Wissenschaftliche Forschungsanwendungen
Dabigatran hat eine große Bandbreite an Anwendungen in der wissenschaftlichen Forschung. In der Medizin wird es verwendet, um thromboembolische Ereignisse und Schlaganfälle bei Patienten mit Vorhofflimmern zu verhindern . Es wird auch zur Behandlung von tiefer Venenthrombose und Lungenembolie eingesetzt . In der biologischen Forschung wird this compound verwendet, um die Gerinnungskaskade und die Thrombininhibition zu untersuchen . Darüber hinaus findet es in der pharmazeutischen Industrie Anwendung bei der Entwicklung neuer Antikoagulanzien .
Wirkmechanismus
This compound wirkt, indem es Thrombin hemmt, eine Serinprotease, die eine Schlüsselrolle in der Gerinnungskaskade spielt . Durch die Bindung an Thrombin verhindert this compound die Umwandlung von Fibrinogen in Fibrin, wodurch die Gerinnselbildung gehemmt wird . Dieser Mechanismus macht es effektiv bei der Reduzierung des Risikos von Schlaganfällen und anderen thromboembolischen Ereignissen .
Biochemische Analyse
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.
Vorbereitungsmethoden
Die Synthese von Dabigatran umfasst mehrere Schritte. Ein Verfahren umfasst die Kondensation von 4-Aminobenzamidin mit Hexylchlorformiat, um N-n-Hexyl-4-aminobenzamidin-carbamate zu erhalten . Dieser Zwischenstoff wird dann weiter mit R1CH2COOH umgesetzt, um 2-(4-(N’-Hexylformiat)amidino)anilin)essigsäure zu erzeugen . Industrielle Produktionsverfahren beinhalten häufig die Verwendung von kristallinen Zwischenprodukten, um die Reinheit und Ausbeute zu gewährleisten .
Analyse Chemischer Reaktionen
Dabigatran unterliegt verschiedenen chemischen Reaktionen, darunter nucleophile Substitution und Hydrolyse. So führt die nucleophile Substitution von Amidin mit n-Hexyl-4-nitrophenylcarbonat zur Bildung von this compound-Base . Häufig verwendete Reagenzien bei diesen Reaktionen sind Hexylchlorformiat und Methansulfonsäure . Das Hauptprodukt, das bei diesen Reaktionen entsteht, ist this compound Etexilat Mesylat .
Vergleich Mit ähnlichen Verbindungen
Dabigatran wird oft mit anderen Antikoagulanzien wie Apixaban, Rivaroxaban und Edoxaban verglichen . Im Gegensatz zu Warfarin benötigt this compound keine regelmäßige Blutüberwachung und hat weniger Arzneimittelwechselwirkungen . Im Vergleich zu Rivaroxaban und Edoxaban hat this compound ein geringeres Risiko für schwere Blutungen . Apixaban hingegen hat sich im Vergleich zu this compound als etwas sicherer erwiesen .
Ähnliche Verbindungen umfassen:
- Apixaban
- Rivaroxaban
- Edoxaban
- Warfarin
Diese Verbindungen werden wie this compound als Antikoagulanzien eingesetzt, unterscheiden sich jedoch in ihrem Wirkmechanismus, ihren Nebenwirkungen und ihren Überwachungsanforderungen .
Eigenschaften
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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Synthesis routes and methods II
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Retrosynthesis Analysis
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