Glimepiride
Overview
Description
Glimepiride is an antidiabetic medication within the sulfonylurea class, primarily prescribed for the management of type 2 diabetes mellitus. It is regarded as a second-line option compared to metformin, due to metformin’s well-established safety and efficacy . This compound works predominantly by increasing the amount of insulin released from the pancreas . It was patented in 1979 and approved for medical use in 1995 .
Mechanism of Action
Target of Action
Glimepiride, a second-generation sulfonylurea drug, primarily targets the pancreatic beta cells . These cells play a crucial role in the regulation of blood glucose levels by secreting insulin, a hormone that facilitates the uptake of glucose into cells .
Mode of Action
This compound stimulates the secretion of insulin granules from pancreatic islet beta cells by blocking ATP-sensitive potassium channels (KATP channels) and causing depolarization of the beta cells . This action results in an increase in insulin levels, which in turn promotes the uptake of glucose into cells, thereby lowering blood glucose levels .
Biochemical Pathways
The primary biochemical pathway affected by this compound is the insulin signaling pathway. By stimulating the release of insulin, this compound enhances the insulin-mediated peripheral glucose uptake . This leads to a decrease in blood glucose levels, which is the primary goal in the management of type 2 diabetes mellitus .
Pharmacokinetics
This compound exhibits excellent pharmacokinetic properties. It is completely absorbed after oral administration, with peak plasma concentrations reached within 2 to 3 hours . It has a high protein binding rate of over 99.5% . This compound is metabolized in the liver through the CYP2C9 enzyme and has an elimination half-life of 5-8 hours . It is excreted in urine (~60%) and feces (~40%) . These properties contribute to its once-daily dosing regimen .
Result of Action
The primary molecular effect of this compound is the increased secretion of insulin from pancreatic beta cells . On a cellular level, this leads to an increase in the uptake of glucose into cells, resulting in a decrease in blood glucose levels . This compound has been associated with a lower risk of developing hypoglycemia and weight gain in clinical trials, as well as fewer cardiovascular effects than other sulfonylureas due to minimal effects on ischemic preconditioning of cardiac myocytes .
Action Environment
The efficacy and stability of this compound can be influenced by various environmental factors. For instance, lifestyle modifications such as diet and exercise are recommended in conjunction with the use of this compound for optimal glycemic control . Furthermore, the presence of adequate insulin synthesis is a prerequisite for the effective action of this compound .
Biochemical Analysis
Biochemical Properties
Glimepiride stimulates insulin release from pancreatic β-cells and may act via extrapancreatic mechanisms . It is administered once daily to patients with type 2 diabetes mellitus in whom glycemic control is not achieved by diet and exercise alone .
Cellular Effects
This compound lowers blood glucose by stimulating insulin secretions from functioning pancreatic beta cells and by inducing extra-pancreatic effects, thereby decreasing insulin resistance . It potentially binds to ATP-sensitive potassium channel receptors on the pancreatic beta cell surface, causing depolarization of the membrane which stimulates calcium ion influx through voltage-sensitive calcium channels .
Molecular Mechanism
The increase in intracellular calcium ion concentration induced by this compound triggers the secretion of insulin . This compound attaches itself to receptors on the surface of pancreatic ß-cells that are dependent on adenosine triphosphate (ATP). Insulin release, a calcium influx, and potassium outflow result from the closure of these channels and membrane depolarization .
Temporal Effects in Laboratory Settings
A new crystalline form of this compound has been synthesized and characterized, showing different solubility and melting properties from the reported polymorphs . The crystal structure of this new form is more thermodynamically stable than the previously reported forms .
Dosage Effects in Animal Models
Specific dosage effects of this compound in animal models are not mentioned in the available literature. Like other sulfonylureas, this compound is used based on its well-established glucose-lowering action .
Metabolic Pathways
This compound is involved in the metabolic pathway that regulates blood glucose levels. It stimulates insulin release from pancreatic β-cells, which plays a crucial role in glucose metabolism .
Preparation Methods
Synthetic Routes and Reaction Conditions
Glimepiride is synthesized through a multi-step process involving several intermediates. The key steps include the formation of the pyrrole ring and the attachment of the sulfonylurea group. The reaction conditions typically involve the use of organic solvents, catalysts, and controlled temperatures to ensure the desired chemical transformations .
Industrial Production Methods
Industrial production of this compound involves large-scale synthesis using optimized reaction conditions to maximize yield and purity. The process includes purification steps such as crystallization and filtration to obtain the final product in a form suitable for pharmaceutical use .
Chemical Reactions Analysis
Types of Reactions
Glimepiride undergoes various chemical reactions, including:
Oxidation: Involves the addition of oxygen or the removal of hydrogen.
Reduction: Involves the addition of hydrogen or the removal of oxygen.
Substitution: Involves the replacement of one functional group with another.
Common Reagents and Conditions
Common reagents used in these reactions include oxidizing agents like potassium permanganate, reducing agents like sodium borohydride, and various catalysts to facilitate the reactions .
Major Products Formed
The major products formed from these reactions depend on the specific conditions and reagents used. For example, oxidation of this compound can lead to the formation of sulfoxides or sulfones .
Scientific Research Applications
Glimepiride has a wide range of scientific research applications:
Comparison with Similar Compounds
Similar Compounds
Uniqueness
Glimepiride is unique among sulfonylureas due to its longer duration of action and lower risk of hypoglycemia compared to other second-generation sulfonylureas . It also has fewer cardiovascular effects, making it a safer option for patients with cardiovascular concerns .
Properties
IUPAC Name |
4-ethyl-3-methyl-N-[2-[4-[(4-methylcyclohexyl)carbamoylsulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C24H34N4O5S/c1-4-21-17(3)15-28(22(21)29)24(31)25-14-13-18-7-11-20(12-8-18)34(32,33)27-23(30)26-19-9-5-16(2)6-10-19/h7-8,11-12,16,19H,4-6,9-10,13-15H2,1-3H3,(H,25,31)(H2,26,27,30) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
WIGIZIANZCJQQY-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCC1=C(CN(C1=O)C(=O)NCCC2=CC=C(C=C2)S(=O)(=O)NC(=O)NC3CCC(CC3)C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C24H34N4O5S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID5040675, DTXSID20861130 |
Source
|
| Record name | Glimepiride | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID5040675 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID20861130 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
490.6 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 | Glimepiride | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014367 | |
| 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 |
>73.6 [ug/mL] (The mean of the results at pH 7.4), Partly miscible, 3.84e-02 g/L |
Source
|
| Record name | SID49648856 | |
| 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 | Glimepiride | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00222 | |
| 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. | |
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| Record name | Glimepiride | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014367 | |
| 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 |
ATP-sensitive potassium channels on pancreatic beta cells that are gated by intracellular ATP and ADP. The hetero-octomeric complex of the channel is composed of four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor (SUR) subunits. Alternative splicing allows the formation of channels composed of varying subunit isoforms expressed at different concentrations in different tissues. In pancreatic beta cells, ATP-sensitive potassium channels play a role as essential metabolic sensors and regulators that couple membrane excitability with glucose-stimulated insulin secretion (GSIS). When there is a decrease in the ATP:ADP ratio, the channels are activated and open, leading to K+ efflux from the cell, membrane hyperpolarization, and suppression of insulin secretion. In contrast, increased uptake of glucose into the cell leads to elevated intracellular ATP:ADP ratio, leading to the closure of channels and membrane depolarization. Depolarization leads to activation and opening of the voltage-dependent Ca2+ channels and consequently an influx of calcium ions into the cell. Elevated intracellular calcium levels causes the contraction of the filaments of actomyosin responsible for the exocytosis of insulin granules stored in vesicles. Glimepiride blocks the ATP-sensitive potassium channel by binding non-specifically to the B sites of both sulfonylurea receptor-1 (SUR1) and sulfonylurea receptor-2A (SUR2A) subunits as well as the A site of SUR1 subunit of the channel to promote insulin secretion from the beta cell. |
Source
|
| Record name | Glimepiride | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00222 | |
| 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. | |
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CAS No. |
261361-60-8, 93479-97-1, 684286-46-2 |
Source
|
| Record name | 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=261361-60-8 | |
| 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. | |
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| Record name | Glimepiride [USAN:USP:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0093479971 | |
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| Record name | Glimepiride, cis- | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0684286462 | |
| 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 | Glimepiride | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00222 | |
| 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. | |
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| Record name | glimepiride | |
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| Record name | Glimepiride | |
| Source | EPA DSSTox | |
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| Record name | 3-Ethyl-2,5-dihydro-4-methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]sulfonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1-carboxamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID20861130 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Glimepiride | |
| Source | European Chemicals Agency (ECHA) | |
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| Record name | GLIMEPIRIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/6KY687524K | |
| 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. | |
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| Record name | GLIMEPIRIDE, CIS- | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/24T6XIR2MZ | |
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| Record name | Glimepiride | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014367 | |
| 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 |
207 °C |
Source
|
| Record name | Glimepiride | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00222 | |
| 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 | Glimepiride | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014367 | |
| 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
AI-Powered Synthesis Planning: Our tool employs the Template_relevance Pistachio, Template_relevance Bkms_metabolic, Template_relevance Pistachio_ringbreaker, Template_relevance Reaxys, Template_relevance Reaxys_biocatalysis model, leveraging a vast database of chemical reactions to predict feasible synthetic routes.
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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: What is the primary mechanism of action of Glimepiride?
A1: this compound is a third-generation sulfonylurea derivative that acts as an oral anti-hyperglycemic agent. Its primary mechanism of action involves binding to sulfonylurea receptors (SUR1) on pancreatic β-cells. [, ] This binding leads to the closure of ATP-sensitive potassium (KATP) channels, causing membrane depolarization and subsequent opening of voltage-gated calcium channels. The influx of calcium ions triggers the exocytosis of insulin-containing granules, leading to increased insulin secretion and ultimately lowering blood glucose levels. [, , , , , , , ]
Q2: What is the molecular formula and weight of this compound?
A4: The molecular formula of this compound is C24H34N4O5S, and its molecular weight is 490.62 g/mol. [, ]
Q3: Are there different polymorphic forms of this compound, and how do they differ?
A5: Yes, this compound exists in different polymorphic forms. Research has identified three distinct polymorphs: Form I, Form II, and a novel Form III. [] These forms differ in their physicochemical properties, including solubility, melting point, and stability. Notably, Form III exhibits a higher melting point (276.2°C) compared to Form I and Form II, and its X-ray diffraction pattern distinguishes it from the other forms. []
Q4: What spectroscopic techniques are commonly employed to characterize this compound?
A4: Various spectroscopic techniques are employed in the characterization and analysis of this compound. These include:
- Fourier-transform infrared (FTIR) spectroscopy: FTIR helps identify functional groups and assess drug-excipient compatibility in formulations. [, , ]
- X-ray diffraction (XRD): XRD is crucial for identifying and characterizing the different polymorphic forms of this compound. [, , ]
- Differential scanning calorimetry (DSC): DSC provides insights into thermal transitions and polymorphic transformations of this compound. [, ]
Q5: How does this compound perform in solid dispersions with polyethylene glycol (PEG)?
A7: Studies have shown that this compound exhibits enhanced solubility and dissolution rates when formulated as solid dispersions with PEG 20000. [, ] The solubility of this compound increases proportionally with the concentration of PEG 20000 in a pH 7.4 buffer. [] This improvement is attributed to the amorphization of this compound within the PEG matrix, as confirmed by XRD studies. []
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
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