达比加群
概述
描述
作用机制
科学研究应用
达比加群酯具有广泛的科学研究应用。 在医学上，它用于预防患有心房颤动的患者的栓塞事件和中风 . 它还用于治疗深静脉血栓形成和肺栓塞 . 在生物学研究中，达比加群酯用于研究凝血级联和凝血酶抑制 . 此外，它在制药行业有应用，用于开发新的抗凝剂疗法 .
生化分析
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 . Dabigatran binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors .
Cellular Effects
Dabigatran 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
Dabigatran 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
Dabigatran has a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring . Peak plasma concentrations of dabigatran 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, dabigatran 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, dabigatran was found to provide acceptable anticoagulation similar to heparin to prevent thrombosis .
Metabolic Pathways
Dabigatran is metabolized primarily by esterases . It is not metabolized by cytochrome P450 isoenzymes . The predominant metabolic reaction is esterase-mediated hydrolysis of dabigatran etexilate to dabigatran .
Transport and Distribution
Dabigatran etexilate is a substrate of esterases and P-glycoprotein (P-gp) . After oral administration, it is rapidly absorbed and converted to its active form, dabigatran .
Subcellular Localization
The subcellular localization of dabigatran 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 dabigatran would be localized in areas of the cell involved in these processes.
准备方法
化学反应分析
达比加群酯会发生各种化学反应，包括亲核取代反应和水解反应。 例如，脒与正己基-4-硝基苯基碳酸酯的亲核取代反应会导致达比加群酯碱的形成 . 这些反应中常用的试剂包括己基氯甲酸酯和甲磺酸 . 这些反应产生的主要产物是达比加群酯依替酯甲磺酸盐 .
相似化合物的比较
达比加群酯通常与其他抗凝剂如阿哌沙班、利伐沙班和依度沙班进行比较 . 与华法林不同，达比加群酯不需要定期进行血液监测，且药物相互作用更少 . 与利伐沙班和依度沙班相比，达比加群酯发生严重出血的风险较低 . 然而，阿哌沙班已被发现具有比达比加群酯更有利的安全性 .
类似的化合物包括：
- 阿哌沙班
- 利伐沙班
- 依度沙班
- 华法林
属性
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
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| 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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