Clopidogrel
Overview
Description
Clopidogrel is an antiplatelet medication primarily used to reduce the risk of heart disease and stroke in individuals at high risk. It is often prescribed in combination with aspirin for patients who have experienced heart attacks or have undergone coronary artery stent placement . This compound belongs to the thienopyridine class of antiplatelet agents and works by inhibiting platelet aggregation .
Scientific Research Applications
Clopidogrel has a wide range of scientific research applications:
Chemistry: this compound is used as a model compound in studies related to antiplatelet agents and their mechanisms of action.
Biology: Research on this compound focuses on its effects on platelet function and its role in preventing thrombotic events.
Medicine: this compound is extensively studied for its clinical applications in preventing heart attacks, strokes, and other cardiovascular events.
Mechanism of Action
Target of Action
Clopidogrel is an antiplatelet agent that primarily targets the P2Y12 subtype of ADP receptors on platelets . These receptors play a crucial role in platelet activation and aggregation, which are key processes in the formation of blood clots .
Mode of Action
This compound is a prodrug, meaning it requires metabolic activation to become effective . It is activated via a two-step reaction to an active thiol-containing metabolite . This active form irreversibly binds to P2Y12 ADP receptors on platelets . This binding prevents ADP from activating the glycoprotein GPIIb/IIIa complex, thereby reducing platelet aggregation .
Biochemical Pathways
This compound’s activation involves several enzymes, including CYP1A2 and CYP2B6, which metabolize this compound to 2-oxo-clopidogrel . Other enzymes, such as CYP2C19 and CYP3A4, are also involved, but their roles are less consistent and depend on the specific test system and laboratory . All major drug-metabolizing CYP enzymes can convert 2-oxo-clopidogrel to sulfenic acid intermediates, which subsequently form the active thiol metabolite .
Pharmacokinetics
This compound has a bioavailability of over 50% . It is metabolized in the liver and has an onset of action of about 2 hours . The elimination half-life of its inactive metabolite is 7-8 hours . This compound is excreted 50% through the kidneys and 46% through the bile duct .
Result of Action
The molecular effect of this compound’s action is the irreversible inhibition of the P2Y12 receptor on platelets . This prevents the activation of the glycoprotein GPIIb/IIIa complex, reducing platelet aggregation . On a cellular level, this results in a reduced ability of the platelets to form blood clots, thereby reducing the risk of thrombotic events .
Action Environment
Environmental factors, including genetic variations and non-genetic factors such as demographics, disease complications, and drug-drug interactions, can influence this compound’s action, efficacy, and stability . Genetic polymorphisms in the genes encoding this compound’s transporter, metabolizing enzymes, and target receptor can interfere with its antiplatelet activity . Non-genetic factors such as demographics, disease complications, and drug-drug interactions can also impair the antiplatelet effect of this compound .
Safety and Hazards
Clopidogrel may increase the risk of serious bleeding during a surgery, other medical procedures, or some kinds of dental work . It can cause severe skin burns and eye damage. Toxic to aquatic life with long-lasting effects . Adverse effects associated with therapeutic use include gastrointestinal bleeding, gastrointestinal disturbances, nausea, diarrhea, bleeding, discoloration of skin, fever, pain, swelling, dizziness, difficulty breathing .
Future Directions
There is substantial inter-individual variability in the response to clopidogrel treatment, in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors . This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19, which affect the pharmacokinetics of this compound . While the US Food and Drug Administration has issued a boxed warning for CYP2C19 poor metabolizers because of potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases, and drug–drug interactions, may all contribute to the overall between-subject variability in treatment response . Therefore, more specific antiplatelet treatment regimens, which may include more potent agents or a combination with other antiplatelet drugs, are warranted in the future .
Biochemical Analysis
Biochemical Properties
Clopidogrel’s biochemical target is the purinergic receptor P2Y12 . In platelets, the P2Y12 receptor is coupled to the inhibitory G-protein Gi . The inhibition of platelet response to ADP is observed within 12 hours after this compound intake .
Cellular Effects
This compound has significant effects on platelets. It inhibits the function of the P2Y12 receptor, thereby preventing spontaneous platelet aggregation after percutaneous transluminal coronary angioplasty .
Molecular Mechanism
This compound is a prodrug that requires biotransformation into its active thiol metabolite by the cytochrome P450 enzymes . The active metabolite then inhibits the P2Y12 receptor on platelets, preventing platelet aggregation .
Temporal Effects in Laboratory Settings
In laboratory settings, aggregometry and VASP phosphorylation revealed a loss of platelet response to ADP within 12 hours after this compound intake . The phosphorylation status of VASP correlated with the inhibition of platelet aggregation .
Metabolic Pathways
This compound is metabolized by the cytochrome P450 enzymes, primarily CYP2C19, into its active form . The active metabolite then inhibits the P2Y12 receptor, affecting platelet aggregation .
Preparation Methods
Synthetic Routes and Reaction Conditions: Clopidogrel can be synthesized through various methods. One common approach involves the racemization of R(-) this compound using a powered anhydrous base in one or more solvents . Another method includes the precipitation of this compound bisulfate from a solvent mixture of methanol and acetone in the presence of sulfuric acid at a temperature of 25-40°C . Additionally, this compound can be prepared by reacting L-2-chlorophenylglycine with methanol to generate L-2-chlorophenylglycine methyl ester, followed by a series of reactions to obtain this compound .
Industrial Production Methods: Industrial production of this compound often involves the resolution of racemic this compound to obtain the active S(+) enantiomer. This process includes the use of specific reagents and conditions to ensure high yield and purity .
Chemical Reactions Analysis
Types of Reactions: Clopidogrel undergoes several types of chemical reactions, including oxidation, reduction, and substitution.
Common Reagents and Conditions:
Oxidation: this compound can be oxidized using reagents such as hydrogen peroxide or potassium permanganate under controlled conditions.
Reduction: Reduction reactions may involve the use of reducing agents like sodium borohydride or lithium aluminum hydride.
Substitution: Substitution reactions often require nucleophiles such as halides or amines in the presence of suitable catalysts.
Major Products: The major products formed from these reactions depend on the specific reagents and conditions used. For example, oxidation of this compound can lead to the formation of various oxidized metabolites, while substitution reactions can yield different substituted derivatives of this compound.
Comparison with Similar Compounds
Ticlopidine: Another thienopyridine antiplatelet agent, but with a higher incidence of adverse effects.
Prasugrel: A newer thienopyridine with a more rapid onset of action and greater potency compared to clopidogrel.
Ticagrelor: A non-thienopyridine antiplatelet agent that provides reversible inhibition of the P2Y12 receptor.
Uniqueness of this compound: this compound is unique due to its irreversible binding to the P2Y12 receptor, providing long-lasting antiplatelet effects. It is also widely used in clinical practice due to its proven efficacy and safety profile .
Properties
IUPAC Name |
methyl (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
GKTWGGQPFAXNFI-HNNXBMFYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COC(=O)C(C1=CC=CC=C1Cl)N2CCC3=C(C2)C=CS3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
COC(=O)[C@H](C1=CC=CC=C1Cl)N2CCC3=C(C2)C=CS3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C16H16ClNO2S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID6022848 |
Source
|
| Record name | Clopidogrel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6022848 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
321.8 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Clopidogrel | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005011 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
15.1 [ug/mL] (The mean of the results at pH 7.4) |
Source
|
| Record name | SID49666423 | |
| Source | Burnham Center for Chemical Genomics | |
| URL | https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table | |
| Description | Aqueous solubility in buffer at pH 7.4 | |
Mechanism of Action |
Clopidogrel is metabolized to its active form by carboxylesterase-1. The active form is a platelet inhibitor that irreversibly binds to P2Y12 ADP receptors on platelets. This binding prevents ADP binding to P2Y12 receptors, activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation., Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP., The P2Y12 receptor plays a crucial role in the regulation of platelet activation by several agonists, which is irreversibly antagonized by the active metabolite of clopidogrel, a widely used anti-thrombotic drug. In this study, we investigated whether reduction of platelet reactivity leads to reduced inflammatory responses using a rat model of erosive arthritis. We evaluated the effect of clopidogrel on inflammation in Lewis rats in a peptidoglycan polysaccharide (PG-PS)-induced arthritis model with four groups of rats: 1) untreated, 2) clopidogrel-treated, 3) PG-PS-induced, and 4) PG-PS-induced and clopidogrel-treated. There were significant differences between the PG-PS+clopidogrel group when compared to the PG-PS group including: increased joint diameter and clinical manifestations of inflammation, elevated plasma levels of pro-inflammatory cytokines (IL-1 beta, interferon (IFN) gamma, and IL-6), an elevated neutrophil blood count and an increased circulating platelet count. Plasma levels of IL-10 were significantly lower in the PG-PS+clopidogrel group compared to the PG-PS group. Plasma levels of platelet factor 4 (PF4) were elevated in both the PG-PS and the PG-PS+clopidogrel groups, however PF4 levels showed no difference upon clopidogrel treatment, suggesting that the pro- inflammatory effect of clopidogrel may be due to its action on cells other than platelets. Histology indicated an increase in leukocyte infiltration at the inflammatory area of the joint, increased pannus formation, blood vessel proliferation, subsynovial fibrosis and cartilage erosion upon treatment with clopidogrel in PG-PS-induced arthritis animals. In summary, animals treated with clopidogrel showed a pro-inflammatory effect in the PG-PS-induced arthritis animal model, which might not be mediated by platelets. |
Source
|
| Record name | Clopidogrel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00758 | |
| 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 | CLOPIDOGREL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7430 | |
| 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 |
Colorless oil | |
CAS No. |
113665-84-2 |
Source
|
| Record name | Clopidogrel | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=113665-84-2 | |
| 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 | Clopidogrel [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0113665842 | |
| 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 | Clopidogrel | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00758 | |
| 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 | Clopidogrel | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID6022848 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Thieno[3,2-c]pyridine-5(4H)-acetic acid, α-(2-chlorophenyl)-6,7-dihydro-, methyl ester, (αS) | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.127.841 | |
| 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 | CLOPIDOGREL | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/A74586SNO7 | |
| 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 | CLOPIDOGREL | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7430 | |
| 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. | |
| Record name | Clopidogrel | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0005011 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Synthesis routes and methods I
Procedure details
Synthesis routes and methods II
Procedure details
Retrosynthesis Analysis
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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
Q1: How does Clopidogrel interact with its target and what are the downstream effects?
A1: this compound is a prodrug that requires metabolic activation to exert its antiplatelet effect. Its active metabolite irreversibly binds to the platelet adenosine diphosphate (ADP) receptor P2Y12. [, , , , ] This binding prevents ADP-induced platelet activation and aggregation, crucial steps in thrombus formation. [, , , ] this compound's action ultimately reduces the risk of atherothrombotic events like stroke, myocardial infarction, and cardiovascular death. [, , , , , , , , ]
Q2: Why is P2Y12 inhibition important for antiplatelet therapy?
A2: The P2Y12 receptor on platelets plays a crucial role in amplifying platelet activation initiated by various agonists, including ADP. [, , , , ] Inhibiting P2Y12 effectively blocks this amplification, leading to a more sustained reduction in platelet aggregation and thrombus formation.
Q3: How does this compound compare to Aspirin in terms of platelet inhibition?
A3: While both this compound and Aspirin are antiplatelet agents, they target different pathways. Aspirin inhibits the cyclooxygenase enzyme, thereby blocking Thromboxane A2 synthesis, a potent platelet activator. This compound, on the other hand, blocks the P2Y12 receptor, preventing ADP-induced platelet activation. [, , , ] Combining both agents can result in synergistic platelet inhibition, especially in acute coronary syndromes. [, , , , , ]
Q4: What is the molecular formula and weight of this compound?
A4: The molecular formula of this compound is C16H16ClNO2S, and its molecular weight is 321.82 g/mol.
Q5: How is this compound metabolized, and how does this impact its effectiveness?
A5: this compound is a prodrug, meaning it needs to be metabolized in the liver to become active. This process involves several enzymes, particularly CYP2C19. [, , , , , , ] Genetic variations in CYP2C19 can significantly impact this compound metabolism and, consequently, its effectiveness. [, , , , , , ]
Q6: What is this compound resistance, and how does it develop?
A6: this compound resistance refers to an inadequate platelet inhibition despite taking this compound. [, , , ] It can result from factors such as genetic polymorphisms in CYP2C19, drug interactions (e.g., with proton pump inhibitors), diabetes, obesity, and individual variability in platelet reactivity. [, , , , , , , ]
Q7: What are the main clinical uses of this compound?
A8: this compound is primarily used to prevent atherothrombotic events in patients with acute coronary syndromes (including unstable angina and myocardial infarction), those who have undergone percutaneous coronary interventions (PCI), and individuals with a history of stroke or peripheral artery disease. [, , , , , , , , ]
Q8: What are the advantages of using this compound as a loading dose before PCI?
A9: Administering a loading dose of this compound before PCI helps achieve rapid and effective platelet inhibition, reducing the risk of stent thrombosis and other ischemic complications. [, , , ] Clinical trials have demonstrated a greater reduction in ischemic events when this compound is given as a loading dose compared to placebo or lower doses. [, , ]
Q9: What are the implications of the interaction between this compound and Proton Pump Inhibitors (PPIs)?
A10: PPIs, commonly prescribed to prevent gastrointestinal bleeding in patients on dual antiplatelet therapy, can inhibit the CYP2C19 enzyme responsible for this compound activation. [, , , ] This interaction may reduce this compound's effectiveness and potentially increase the risk of adverse cardiovascular events in some patients. [, , , ]
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