Gliclazida
Descripción general
Descripción
La gliclazida es un medicamento antidiabético de tipo sulfonilurea que se utiliza para tratar la diabetes mellitus tipo 2 . Se administra por vía oral y es particularmente útil cuando los cambios en la dieta, el ejercicio y la pérdida de peso son insuficientes para controlar los niveles de azúcar en sangre . La this compound funciona principalmente aumentando la liberación de insulina del páncreas . Se patentó en 1966 y se aprobó para uso médico en 1972 .
Aplicaciones Científicas De Investigación
La gliclazida tiene varias aplicaciones de investigación científica:
Química: Se utiliza como compuesto modelo en estudios de química de sulfonilurea y sus derivados.
Biología: La this compound se estudia por sus efectos sobre las células beta pancreáticas y la secreción de insulina.
Industria: La this compound se utiliza en la industria farmacéutica para la producción de medicamentos antidiabéticos.
Mecanismo De Acción
La gliclazida ejerce sus efectos uniéndose al receptor de sulfonilurea en las células beta pancreáticas. Esta unión bloquea los canales de potasio sensibles al ATP, lo que lleva a la despolarización celular y la posterior apertura de los canales de calcio dependientes del voltaje. La entrada de iones calcio desencadena la liberación de insulina . Además, la this compound aumenta la utilización periférica de glucosa y disminuye la gluconeogénesis hepática .
Análisis Bioquímico
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 .
Métodos De Preparación
La síntesis de la gliclazida implica varios pasos. Un método incluye la reacción de p-toluensulfonilurea con hidrato de hidrazina para obtener un compuesto intermedio, que luego se hace reaccionar con anhídrido 1,2-ciclopentano dicarboxílico para formar otro intermedio. Este intermedio finalmente se reduce para producir this compound . Otro método implica preparar N-amino-1,2-ciclopentano ftalamida haciendo reaccionar anhídrido 1,2-ciclopentano ftálico con hidrato de hidrazina, seguido de reducción y posterior reacción con metilfenilsulfonilurea .
Análisis De Reacciones Químicas
La gliclazida experimenta varias reacciones químicas, que incluyen:
Oxidación: La this compound puede oxidarse para formar sulfoxidos y sulfonas.
Reducción: La reducción de la this compound puede conducir a la formación de aminas.
Sustitución: La this compound puede sufrir reacciones de sustitución nucleofílica, particularmente en el grupo sulfonilo.
Los reactivos comunes utilizados en estas reacciones incluyen agentes oxidantes como el peróxido de hidrógeno y agentes reductores como el borohidruro de sodio . Los productos principales formados a partir de estas reacciones dependen de las condiciones específicas y los reactivos utilizados.
Comparación Con Compuestos Similares
La gliclazida es parte de la clase de medicamentos de sulfonilurea, que también incluye glimepirida, gliburida y glipizida . En comparación con estos compuestos, la this compound tiene un menor riesgo de causar hipoglucemia y se asocia con menos efectos secundarios . También tiene una estructura química única que contribuye a sus propiedades farmacocinéticas y farmacodinámicas específicas .
Propiedades
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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