Gliclazide
Overview
Description
Gliclazide is a sulfonylurea type of anti-diabetic medication used to treat type 2 diabetes mellitus . It is taken orally and is particularly useful when dietary changes, exercise, and weight loss are insufficient to control blood sugar levels . This compound works primarily by increasing the release of insulin from the pancreas . It was patented in 1966 and approved for medical use in 1972 .
Scientific Research Applications
Gliclazide has several scientific research applications:
Chemistry: It is used as a model compound in studies of sulfonylurea chemistry and its derivatives.
Biology: this compound is studied for its effects on pancreatic beta cells and insulin secretion.
Industry: This compound is used in the pharmaceutical industry for the production of anti-diabetic medications.
Mechanism of Action
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
This compound 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 this compound is the insulin signaling pathway. By stimulating the release of insulin, this compound 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
This compound 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 this compound is approximately 10 hours . These pharmacokinetic properties impact the bioavailability of this compound, influencing its therapeutic efficacy.
Result of Action
The action of this compound 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, this compound 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 this compound can be influenced by various environmental factors. For instance, the risk of hypoglycemia, a potential side effect of this compound, is increased in elderly, debilitated, and malnourished individuals . Furthermore, this compound’s effectiveness can be enhanced when combined with other hypoglycemic agents such as probiotics and bile acids .
Safety and Hazards
Future Directions
Studies of potential new glucose-lowering agents offer the opportunity to safely improve glycaemic control with prolonged efficacy and greater opportunity for therapeutic individualisation . New and ongoing studies will add to the cumulative data on the efficacy and safety of certain sulfonylureas in patients with diabetes .
Biochemical Analysis
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
This compound 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
This compound 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
This compound 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, this compound has shown significant reduction in blood glucose levels . The effects of this compound vary with different dosages, and it has been observed that this compound can lower the HbA1c by 11mmol/mol on average .
Metabolic Pathways
This compound 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
This compound 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 this compound is not clearly defined. Given its mechanism of action, it is likely that this compound interacts with β cells in the pancreas, specifically at the sulfonylurea receptor (SUR1) located on the ATP-sensitive potassium channels .
Preparation Methods
The synthesis of Gliclazide involves several steps. One method includes reacting p-toluenesulfonylurea with hydrazine hydrate to obtain an intermediate compound, which is then reacted with 1,2-cyclopentane dicarboxylic anhydride to form another intermediate. This intermediate is finally reduced to produce this compound . Another method involves preparing N-amino-1,2-cyclopentane phthalic amide by reacting 1,2-cyclopentane phthalic anhydride with hydrazine hydrate, followed by reduction and subsequent reaction with methylphenylsulfonylurea .
Chemical Reactions Analysis
Gliclazide undergoes various chemical reactions, including:
Oxidation: this compound can be oxidized to form sulfoxides and sulfones.
Reduction: Reduction of this compound can lead to the formation of amines.
Substitution: this compound can undergo nucleophilic substitution reactions, particularly at the sulfonyl group.
Common reagents used in these reactions include oxidizing agents like hydrogen peroxide and reducing agents like sodium borohydride . The major products formed from these reactions depend on the specific conditions and reagents used.
Comparison with Similar Compounds
Gliclazide is part of the sulfonylurea class of medications, which also includes glimepiride, glyburide, and glipizide . Compared to these compounds, this compound has a lower risk of causing hypoglycemia and is associated with fewer side effects . It also has a unique chemical structure that contributes to its specific pharmacokinetic and pharmacodynamic properties .
Properties
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: this compound 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 this compound?
A2: Yes, research suggests that this compound 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 this compound on skeletal muscle, enhancing insulin-stimulated glucose metabolism by potentiating insulin action on skeletal muscle glycogen synthase (GS). [, ]
Q3: What is the role of this compound's antioxidant properties in its therapeutic profile?
A3: this compound 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 this compound?
A6: While the provided abstracts do not explicitly mention the molecular formula or weight of this compound, 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 this compound to improve its therapeutic properties?
A7: Although the provided research does not delve into specific structural modifications of this compound, 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 this compound's interaction with other drugs metabolized by the cytochrome P450 system?
A8: this compound's metabolism by CYP2C9 and CYP3A4 raises concerns about potential drug interactions. [, ] Concomitant use of this compound with drugs that inhibit these enzymes, such as clarithromycin, [] might lead to elevated this compound plasma concentrations, increasing the risk of hypoglycemia. [] Conversely, inducers of these enzymes could decrease this compound levels, potentially reducing its effectiveness. [] Close monitoring and dose adjustments might be necessary when this compound is used alongside drugs that interact with CYP2C9 or CYP3A4.
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