Glyburide
Vue d'ensemble
Description
Applications De Recherche Scientifique
Glyburide has a wide range of scientific research applications:
Mécanisme D'action
Le glibénclamide exerce ses effets hypoglycémiants en se liant et en inhibant les canaux potassiques sensibles à l’ATP sur les cellules bêta pancréatiques. Cette inhibition conduit à la fermeture de ces canaux, ce qui entraîne une dépolarisation de la membrane cellulaire et l’ouverture subséquente des canaux calciques dépendants du voltage. L’afflux d’ions calcium déclenche la libération d’insuline par les cellules bêta, ce qui abaisse la glycémie .
Composés similaires :
Unicité du glibénclamide : Le glibénclamide est unique parmi les sulfonylurées en raison de son profil pharmacocinétique équilibré, qui lui confère une durée d’action prolongée tout en maintenant un risque relativement faible d’hypoglycémie. Sa voie d’excrétion double (urine et fèces) le distingue également des autres sulfonylurées .
Analyse Biochimique
Biochemical Properties
By inhibiting these channels, Glyburide causes an increase in intracellular potassium and calcium ion concentrations . This biochemical interaction triggers the release of insulin, thereby playing a crucial role in the regulation of blood glucose levels .
Cellular Effects
This compound exerts significant effects on various types of cells, most notably the beta cells in the pancreas. It stimulates insulin secretion through the closure of ATP-sensitive potassium channels on these beta cells . This action raises intracellular potassium and calcium ion concentrations, which in turn triggers the release of insulin . The increased insulin helps to lower blood glucose levels, thereby managing the symptoms of type 2 diabetes .
Molecular Mechanism
The molecular mechanism of this compound involves its binding to and inhibition of the ATP-sensitive potassium channels (K ATP) inhibitory regulatory subunit sulfonylurea receptor 1 (SUR1) in pancreatic beta cells . This inhibition causes cell membrane depolarization, opening voltage-dependent calcium channels . The influx of calcium ions triggers the release of insulin, which then acts to lower blood glucose levels .
Temporal Effects in Laboratory Settings
In laboratory settings, this compound has been observed to have a long duration of action as it is given once daily . Its effects on cellular function, such as the stimulation of insulin secretion, are therefore sustained over a long period
Dosage Effects in Animal Models
While specific studies on the dosage effects of this compound in animal models are limited, it is known that the drug’s effects can vary with different dosages. For instance, in a study on the brain and whole-body distribution of this compound, it was found that the drug’s distribution, metabolism, and elimination are greatly dependent on organic anion transporting polypeptide (OATP) activity .
Metabolic Pathways
This compound is metabolized mainly by CYP3A4, followed by CYP2C9, CYP2C19, CYP3A7, and CYP3A5 . These enzymes metabolize this compound to various metabolites, including 4-trans-hydroxycyclohexyl this compound (M1), 4-cis-hydroxycyclohexyl this compound (M2a), 3-cis-hydroxycyclohexyl this compound (M2b), 3-trans-hydroxycyclohexyl this compound (M3), 2-trans-hydroxycyclohexyl this compound (M4), and ethylhydroxycyclohexyl this compound (M5) .
Transport and Distribution
This compound’s transport and distribution within cells and tissues are greatly influenced by OATP activity . This transporter plays a critical role in the hepatic uptake of this compound, which is the first step in its hepatic clearance . Moreover, ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and probably multidrug resistance protein 4, work in synergy to limit this compound’s brain uptake .
Subcellular Localization
The subcellular localization of this compound is primarily within the cytoplasm of cells . It is transported into the cell via OATP and is then distributed within the cell to exert its effects
Méthodes De Préparation
Voies de synthèse et conditions de réaction : Le glibénclamide est synthétisé par un processus en plusieurs étapes impliquant la réaction de l’acide 5-chloro-2-méthoxybenzoïque avec le 2-aminoéthylsulfonamide pour former le 5-chloro-2-méthoxy-N-(2-(4-sulfamoylphényl)éthyl)benzamide. Cet intermédiaire est ensuite mis à réagir avec l’isocyanate de cyclohexyle pour produire du glibénclamide .
Méthodes de production industrielle : La production industrielle du glibénclamide implique l’optimisation des conditions de réaction pour garantir un rendement et une pureté élevés. Le processus comprend généralement des étapes telles que la cristallisation, la filtration et le séchage pour obtenir le produit final sous sa forme pure .
Analyse Des Réactions Chimiques
Types de réactions : Le glibénclamide subit diverses réactions chimiques, notamment l’oxydation, la réduction et la substitution.
Réactifs et conditions courants :
Oxydation : Le glibénclamide peut être oxydé à l’aide de réactifs tels que le peroxyde d’hydrogène ou le permanganate de potassium en milieu acide.
Réduction : La réduction du glibénclamide peut être réalisée à l’aide d’agents réducteurs tels que le borohydrure de sodium ou l’hydrure de lithium et d’aluminium.
Substitution : Les réactions de substitution impliquant le glibénclamide utilisent souvent des réactifs tels que les halogènes ou les agents alkylants.
Principaux produits formés : Les principaux produits formés à partir de ces réactions dépendent des réactifs et des conditions spécifiques utilisés. Par exemple, l’oxydation peut produire des dérivés hydroxylés, tandis que la réduction peut produire des produits déchlorés ou déméthylés .
4. Applications de la recherche scientifique
Le glibénclamide a un large éventail d’applications de recherche scientifique :
Comparaison Avec Des Composés Similaires
Uniqueness of this compound: this compound is unique among sulfonylureas due to its balanced pharmacokinetic profile, which provides a prolonged duration of action while maintaining a relatively low risk of hypoglycemia. Its dual excretion pathway (urine and feces) also distinguishes it from other sulfonylureas .
Propriétés
IUPAC Name |
5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxybenzamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C23H28ClN3O5S/c1-32-21-12-9-17(24)15-20(21)22(28)25-14-13-16-7-10-19(11-8-16)33(30,31)27-23(29)26-18-5-3-2-4-6-18/h7-12,15,18H,2-6,13-14H2,1H3,(H,25,28)(H2,26,27,29) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
ZNNLBTZKUZBEKO-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
COC1=C(C=C(C=C1)Cl)C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)NC3CCCCC3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C23H28ClN3O5S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID0037237 |
Source
|
| Record name | Glybenclamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID0037237 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
494.0 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 | Glyburide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015151 | |
| 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 |
2.06e-03 g/L |
Source
|
| Record name | Glyburide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015151 | |
| 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 |
Glyburide belongs to a class of drugs known as sulfonylureas. These drugs act by closing ATP-sensitive potassium channels on pancreatic beta cells. The ATP-sensitive potassium channels on beta cells are known as sulfonylurea receptor 1 (SUR1). Under low glucose concentrations, SUR1 remains open, allowing for potassium ion efflux to create a -70mV membrane potential. Normally SUR1 closes in response to high glucose concentrations, the membrane potential of the cells becomes less negative, the cell depolarizes, voltage gated calcium channels open, calcium ions enter the cell, and the increased intracellular calcium concentration stimulates the release of insulin containing granules. Glyburide bypasses this process by forcing SUR1 closed and stimulating increased insulin secretion. |
Source
|
| Record name | Glyburide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01016 | |
| 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. |
10238-21-8 |
Source
|
| Record name | Glibenclamide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=10238-21-8 | |
| 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 | Glyburide [USAN:USP] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0010238218 | |
| 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 | Glyburide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01016 | |
| 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 | glyburide | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759618 | |
| 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 | Glybenclamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID0037237 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Glibenclamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.030.505 | |
| 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 | GLYBURIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/SX6K58TVWC | |
| 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 | Glyburide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015151 | |
| 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 |
169 - 170 °C |
Source
|
| Record name | Glyburide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01016 | |
| 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 | Glyburide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015151 | |
| 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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|---|---|
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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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