Gliclazid
Übersicht
Beschreibung
Gliclazid ist ein Sulfonylharnstoff-Antidiabetikum, das zur Behandlung von Typ-2-Diabetes mellitus eingesetzt wird . Es wird oral eingenommen und ist besonders nützlich, wenn Ernährungsumstellungen, Bewegung und Gewichtsabnahme nicht ausreichen, um den Blutzuckerspiegel zu kontrollieren . This compound wirkt in erster Linie, indem es die Insulinsekretion aus der Bauchspeicheldrüse erhöht . Es wurde 1966 patentiert und 1972 für die medizinische Verwendung zugelassen .
Wissenschaftliche Forschungsanwendungen
Gliclazide has several scientific research applications:
Chemistry: It is used as a model compound in studies of sulfonylurea chemistry and its derivatives.
Biology: Gliclazide is studied for its effects on pancreatic beta cells and insulin secretion.
Industry: Gliclazide is used in the pharmaceutical industry for the production of anti-diabetic medications.
Wirkmechanismus
Target of Action
Gliclazide primarily targets the β cell sulfonyl urea receptor (SUR1) located in the pancreas . This receptor plays a crucial role in the regulation of insulin secretion .
Mode of Action
Gliclazide binds to the SUR1, subsequently blocking the ATP sensitive potassium channels . This binding results in the closure of these channels, leading to a decrease in potassium efflux, which in turn causes depolarization of the β cells . This depolarization stimulates the release of insulin, enhancing peripheral insulin sensitivity and potentiating insulin release .
Biochemical Pathways
The primary biochemical pathway affected by gliclazide is the insulin signaling pathway. By stimulating the release of insulin, gliclazide increases both basal insulin secretion and meal-stimulated insulin release . It also enhances peripheral glucose utilization, decreases hepatic gluconeogenesis, and may increase the number and sensitivity of insulin receptors .
Pharmacokinetics
Gliclazide exhibits a higher potency and a shorter half-life compared to other sulfonylureas . It is extensively metabolized by the liver, and its metabolites are excreted in both urine (60-70%) and feces (10-20%) . The elimination half-life of gliclazide is approximately 10 hours . These pharmacokinetic properties impact the bioavailability of gliclazide, influencing its therapeutic efficacy.
Result of Action
The action of gliclazide leads to a decrease in fasting plasma glucose, postprandial blood glucose, and glycosylated hemoglobin (HbA1c) levels . These changes reflect improved glucose control over the last 8-10 weeks . Additionally, gliclazide has been shown to have protective effects on high glucose and AGEs-induced damage of glomerular mesangial cells and renal tubular epithelial cells .
Action Environment
The action, efficacy, and stability of gliclazide can be influenced by various environmental factors. For instance, the risk of hypoglycemia, a potential side effect of gliclazide, is increased in elderly, debilitated, and malnourished individuals . Furthermore, gliclazide’s effectiveness can be enhanced when combined with other hypoglycemic agents such as probiotics and bile acids .
Biochemische Analyse
Biochemical Properties
Gliclazide binds to the β cell sulfonylurea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels . The binding results in closure of the channels and leads to a resulting decrease in potassium efflux which leads to depolarization of the β cells .
Cellular Effects
Gliclazide has been shown to protect cells from H2O2-induced cell death, most likely through the inhibition of ROS production . Moreover, the drug restored loss of ΔΨm and diminished intracellular [Ca2+] evoked by H2O2 .
Molecular Mechanism
Gliclazide works by stimulating insulin secretion, which is achieved by blocking the ATP-sensitive potassium channels in the pancreatic β cells . This leads to depolarization of the β cells, which in turn triggers the release of insulin .
Temporal Effects in Laboratory Settings
Gliclazide has a half-life of around 11 hours . It is extensively metabolized by the liver, and its metabolites are excreted in both urine (60-70%) and feces (10-20%) .
Dosage Effects in Animal Models
In diabetic animal models, gliclazide has shown significant reduction in blood glucose levels . The effects of gliclazide vary with different dosages, and it has been observed that gliclazide can lower the HbA1c by 11mmol/mol on average .
Metabolic Pathways
Gliclazide is extensively metabolized in the liver . Less than 1% of the orally administered dose appears unchanged in the urine. Metabolites include oxidized and hydroxylated derivatives, as well as glucuronic acid conjugates .
Transport and Distribution
Gliclazide is taken orally and is absorbed in the gastrointestinal tract . It is then transported to the liver where it is extensively metabolized .
Subcellular Localization
The exact subcellular localization of Gliclazide is not clearly defined. Given its mechanism of action, it is likely that Gliclazide interacts with β cells in the pancreas, specifically at the sulfonylurea receptor (SUR1) located on the ATP-sensitive potassium channels .
Vorbereitungsmethoden
Die Synthese von Gliclazid umfasst mehrere Schritte. Ein Verfahren beinhaltet die Reaktion von p-Toluolsulfonylharnstoff mit Hydrazinhydrat, um eine Zwischenverbindung zu erhalten, die dann mit 1,2-Cyclopentandicarbonsäureanhydrid umgesetzt wird, um eine weitere Zwischenverbindung zu bilden. Diese Zwischenverbindung wird schließlich reduziert, um this compound zu erzeugen . Ein weiteres Verfahren beinhaltet die Herstellung von N-Amino-1,2-Cyclopentanphthalamid durch Reaktion von 1,2-Cyclopentanphthalanhydrid mit Hydrazinhydrat, gefolgt von Reduktion und anschließender Reaktion mit Methylphenylsulfonylharnstoff .
Analyse Chemischer Reaktionen
Gliclazid unterliegt verschiedenen chemischen Reaktionen, darunter:
Oxidation: this compound kann oxidiert werden, um Sulfoxide und Sulfone zu bilden.
Reduktion: Die Reduktion von this compound kann zur Bildung von Aminen führen.
Substitution: this compound kann nucleophile Substitutionsreaktionen eingehen, insbesondere an der Sulfonylgruppe.
Häufig verwendete Reagenzien in diesen Reaktionen sind Oxidationsmittel wie Wasserstoffperoxid und Reduktionsmittel wie Natriumborhydrid . Die wichtigsten Produkte, die bei diesen Reaktionen entstehen, hängen von den spezifischen Bedingungen und Reagenzien ab, die verwendet werden.
Wissenschaftliche Forschungsanwendungen
This compound hat verschiedene wissenschaftliche Forschungsanwendungen:
Chemie: Es wird als Modellverbindung in Studien zur Sulfonylharnstoffchemie und ihren Derivaten verwendet.
Biologie: this compound wird hinsichtlich seiner Auswirkungen auf Pankreas-Betazellen und die Insulinsekretion untersucht.
Industrie: This compound wird in der pharmazeutischen Industrie zur Herstellung von Antidiabetika eingesetzt.
Wirkmechanismus
This compound entfaltet seine Wirkung, indem es an den Sulfonylharnstoffrezeptor auf Pankreas-Betazellen bindet. Diese Bindung blockiert ATP-sensitive Kaliumkanäle, was zu einer Zelldepolarisation und anschließendem Öffnen von spannungsabhängigen Kalziumkanälen führt. Der Einstrom von Kalziumionen löst die Freisetzung von Insulin aus . Zusätzlich erhöht this compound die periphere Glukoseutilisation und verringert die hepatische Glukoneogenese .
Vergleich Mit ähnlichen Verbindungen
Gliclazid gehört zur Klasse der Sulfonylharnstoff-Medikamente, zu denen auch Glimepirid, Glyburid und Glipizid gehören . Im Vergleich zu diesen Verbindungen hat this compound ein geringeres Risiko, Hypoglykämie zu verursachen, und ist mit weniger Nebenwirkungen verbunden . Es hat auch eine einzigartige chemische Struktur, die zu seinen spezifischen pharmakokinetischen und pharmakodynamischen Eigenschaften beiträgt .
Eigenschaften
IUPAC Name |
1-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-3-(4-methylphenyl)sulfonylurea |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C15H21N3O3S/c1-11-5-7-14(8-6-11)22(20,21)17-15(19)16-18-9-12-3-2-4-13(12)10-18/h5-8,12-13H,2-4,9-10H2,1H3,(H2,16,17,19) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
BOVGTQGAOIONJV-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=CC=C(C=C1)S(=O)(=O)NC(=O)NN2CC3CCCC3C2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C15H21N3O3S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID9023095 |
Source
|
| Record name | Gliclazide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9023095 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
323.4 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 | Gliclazide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015252 | |
| 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 |
42.6 [ug/mL] (The mean of the results at pH 7.4), 1.90e-01 g/L |
Source
|
| Record name | SID49646130 | |
| 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 | |
| Record name | Gliclazide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015252 | |
| 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. | |
Mechanism of Action |
Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. |
Source
|
| Record name | Gliclazide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01120 | |
| 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) | |
CAS No. |
21187-98-4 |
Source
|
| Record name | Gliclazide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=21187-98-4 | |
| 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 | Gliclazide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01120 | |
| 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 | gliclazide | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=758673 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Gliclazide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID9023095 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Gliclazide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.040.221 | |
| 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 | Gliclazide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015252 | |
| 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. | |
Melting Point |
180-182, 181 °C |
Source
|
| Record name | Gliclazide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01120 | |
| 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 | Gliclazide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015252 | |
| 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. | |
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 Gliclazide exert its hypoglycemic effect?
A1: Gliclazide primarily acts by binding to sulfonylurea receptors (SUR1) on pancreatic beta-cell membranes. [, , , ] This binding inhibits ATP-sensitive potassium (KATP) channels, leading to membrane depolarization. [] This depolarization opens voltage-gated calcium channels, increasing intracellular calcium levels. [] The rise in calcium triggers the exocytosis of insulin-containing granules, ultimately increasing insulin secretion and lowering blood glucose levels. [, , ]
Q2: Are there extra-pancreatic effects of Gliclazide?
A2: Yes, research suggests that Gliclazide may influence insulin sensitivity in peripheral tissues. Studies have shown that it can increase the sensitivity of muscle cells to insulin by influencing GLUT-4 transporters. [] Furthermore, it may reduce hepatic glucose production and enhance glucose clearance. [] Some studies propose a potential direct effect of Gliclazide on skeletal muscle, enhancing insulin-stimulated glucose metabolism by potentiating insulin action on skeletal muscle glycogen synthase (GS). [, ]
Q3: What is the role of Gliclazide's antioxidant properties in its therapeutic profile?
A3: Gliclazide exhibits free radical scavenging properties, contributing to its potential protective effects against diabetic complications. [] Studies suggest that it can protect pancreatic beta-cells from oxidative damage induced by hydrogen peroxide. [] This protection is attributed to the drug's ability to reduce oxidative stress, possibly through its radical scavenging activity and modulation of antioxidant and stress gene expression. []
Q4: What are the structural characteristics of Gliclazide?
A6: While the provided abstracts do not explicitly mention the molecular formula or weight of Gliclazide, they describe it as a second-generation sulfonylurea derivative. [, , , ] This classification points to the presence of a sulfonylurea bridge (-SO2NHCONH-) in its structure, a common feature among this class of antidiabetic drugs.
Q5: Has research explored modifying the structure of Gliclazide to improve its therapeutic properties?
A7: Although the provided research does not delve into specific structural modifications of Gliclazide, it highlights the significance of its formulation for improving its therapeutic profile. Studies have investigated various formulation strategies, such as solid dispersions, [, ] nanocrystals, [] and microparticles, [, ] to enhance its solubility and dissolution rate, ultimately aiming to improve its bioavailability and efficacy. [, , , , ]
Q6: What are the implications of Gliclazide's interaction with other drugs metabolized by the cytochrome P450 system?
A8: Gliclazide's metabolism by CYP2C9 and CYP3A4 raises concerns about potential drug interactions. [, ] Concomitant use of Gliclazide with drugs that inhibit these enzymes, such as clarithromycin, [] might lead to elevated Gliclazide plasma concentrations, increasing the risk of hypoglycemia. [] Conversely, inducers of these enzymes could decrease Gliclazide levels, potentially reducing its effectiveness. [] Close monitoring and dose adjustments might be necessary when Gliclazide is used alongside drugs that interact with CYP2C9 or CYP3A4.
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