Canagliflozin
Übersicht
Beschreibung
Canagliflozin is a medication primarily used to treat type 2 diabetes mellitus. It belongs to the class of sodium-glucose cotransporter-2 (SGLT2) inhibitors, which work by preventing the reabsorption of glucose in the kidneys, thereby increasing glucose excretion through urine . This mechanism helps in lowering blood sugar levels in individuals with type 2 diabetes. This compound was approved for medical use in the United States, the European Union, and Australia in 2013 .
Wirkmechanismus
Target of Action
Canagliflozin primarily targets the sodium-glucose co-transporter 2 (SGLT2) . SGLT2 is found in the proximal tubules of the kidney and is responsible for the reabsorption of filtered glucose from the renal tubular lumen back into the body .
Mode of Action
This compound works by inhibiting the SGLT2 co-transporter . This inhibition blocks the reabsorption of glucose in the proximal tubule, lowering the renal threshold for glucose and thereby increasing glucose excretion . This mechanism of action is insulin-independent .
Biochemical Pathways
This compound affects several biochemical pathways. It downregulates glycolysis and upregulates fatty acid oxidation . It also influences intestinal fatty acid and bile acid metabolism . Furthermore, it has been shown to induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease .
Pharmacokinetics
This compound is primarily metabolized by UGT enzymes (UGT1A9, UGT2B4) to O-glucuronides (M7 and M5) and minimally by CYP3A4 . Following administration, 41.5% and 10.2% of this compound is eliminated in the feces as this compound and metabolites, respectively, and approximately 33% is eliminated in the urine, mainly as O-glucuronide metabolites .
Result of Action
The end result of this compound administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control . It also reduces HbA1c by approximately 1.0% . Furthermore, it has been shown to ameliorate diabetic kidney disease by inducing fasting-like and aestivation-like metabolic patterns .
Action Environment
The action of this compound can be influenced by various environmental factors. For instance, the drug’s efficacy can be affected by the patient’s diet and exercise regimen . Additionally, the drug’s action may be influenced by the presence of other medications, particularly those that inhibit or induce CYP3A4 .
Wissenschaftliche Forschungsanwendungen
Canagliflozin hat eine große Bandbreite an Anwendungen in der wissenschaftlichen Forschung:
Medizin: Es wird zur Behandlung von Hyperglykämie bei Typ-2-Diabetes mellitus und zur Reduzierung des Risikos für schwerwiegende kardiovaskuläre Ereignisse eingesetzt.
5. Wirkmechanismus
This compound entfaltet seine Wirkung, indem es den Natrium-Glucose-Cotransporter-2 (SGLT2) in den proximalen Tubuli der Nieren hemmt . Diese Hemmung verhindert die Rückresorption von Glucose aus dem renalen Tubuluslumen, was zu einer erhöhten Glukoseexkretion über den Urin führt . Die molekularen Zielstrukturen, die an diesem Mechanismus beteiligt sind, umfassen die SGLT2-Proteine, die für die Glukoserückresorption in den Nieren verantwortlich sind .
Ähnliche Verbindungen:
- Dapagliflozin
- Empagliflozin
- Metformin
- Ozempic (Semaglutid)
Vergleich:
- Wirksamkeit: this compound hat sich gezeigt, dass es eine ähnliche Wirksamkeit bei der Senkung des HbA1c-Spiegels im Vergleich zu Empagliflozin und Dapagliflozin hat . this compound kann eine etwas höhere Wirksamkeit bei der Senkung des HbA1c-Spiegels im Vergleich zu Dapagliflozin haben .
- Sicherheit: Die Sicherheitsprofile von this compound, Dapagliflozin und Empagliflozin sind vergleichbar, wobei häufige Nebenwirkungen Harnwegsinfektionen und Genitalinfektionen umfassen .
- Einzigartigkeit: this compound ist einzigartig in seiner Fähigkeit, Hirnschwellungen bei zerebraler Ischämie zu reduzieren, eine Eigenschaft, die nicht häufig mit anderen SGLT2-Inhibitoren verbunden ist .
Biochemische Analyse
Biochemical Properties
Canagliflozin promotes urinary glucose excretion by inhibiting renal proximal convoluted tubule . It interacts with SGLT2, a low capacity/high affinity Na+/K+ co-transporter predominantly located in proximal convoluted tubules (PCT) of kidneys .
Cellular Effects
This compound has been shown to impact the composition of gut microbiota and metabolites . It mainly increases Muribaculum, Ruminococcaceae_UCG_014, Lachnospiraceae-UCG-001, and decreases ursodeoxycholic acids (UDCA) and hyodeoxycholic acids (HDCA) .
Molecular Mechanism
The molecular mechanism of this compound involves the inhibition of SGLT2, which prevents reabsorption of glucose and thereby stimulates glucose excretion in the urine .
Temporal Effects in Laboratory Settings
The effects of this compound on intestinal flora and metabolites have been studied in diabetic mice over a period of 8 weeks . It was found that this compound significantly increased GLP-1 level and impacted on the composition of gut microbiota and metabolites .
Metabolic Pathways
This compound influences intestinal fatty acid and bile acid (BA) metabolism . It increases fatty acids metabolites in feces .
Vorbereitungsmethoden
Synthetic Routes and Reaction Conditions: The synthesis of canagliflozin involves multiple steps, starting from the preparation of key intermediates. One of the methods includes the formation of a suspension system of this compound in water or a mixed solvent, followed by crystallization . Another method involves dissolving intermediates in solvents like tetrahydrofuran and methanol, followed by hydrolysis using hydrochloric acid .
Industrial Production Methods: Industrial production of this compound typically involves optimizing the solubility and bioavailability of the compound. Techniques such as microemulsion preconcentrates are employed to improve the solubility and oral bioavailability of this compound . The optimized formulation is evaluated for its dissolution rate, permeation rate, and oral bioavailability.
Analyse Chemischer Reaktionen
Arten von Reaktionen: Canagliflozin unterliegt verschiedenen chemischen Reaktionen, einschließlich Oxidation und Glucuronidierung. Die primären Stoffwechselwege beinhalten die Bildung von O-Glucuronid-Metaboliten und Oxidationsprodukten .
Häufige Reagenzien und Bedingungen:
Oxidation: this compound kann oxidiert werden, um Metaboliten wie M8 und M9 zu bilden.
Glucuronidierung: Diese Reaktion beinhaltet die Addition von Glucuronsäure zu this compound, wodurch Metaboliten wie M5, M7 und M17 gebildet werden.
Hauptprodukte: Die Hauptprodukte, die aus diesen Reaktionen gebildet werden, umfassen O-Glucuronid-Metaboliten und Oxidationsprodukte, die dann aus dem Körper ausgeschieden werden .
Vergleich Mit ähnlichen Verbindungen
- Dapagliflozin
- Empagliflozin
- Metformin
- Ozempic (semaglutide)
Comparison:
- Efficacy: Canagliflozin has been shown to have similar efficacy in lowering HbA1c levels compared to empagliflozin and dapagliflozin . this compound may have a slightly higher efficacy at lowering HbA1c compared to dapagliflozin .
- Safety: The safety profiles of this compound, dapagliflozin, and empagliflozin are comparable, with common side effects including urinary tract infections and genital infections .
- Uniqueness: this compound is unique in its ability to reduce brain swelling in cerebral ischemia, a property not commonly associated with other SGLT2 inhibitors .
Eigenschaften
IUPAC Name |
(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C24H25FO5S/c1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
XTNGUQKDFGDXSJ-ZXGKGEBGSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=C(C=C(C=C1)C2C(C(C(C(O2)CO)O)O)O)CC3=CC=C(S3)C4=CC=C(C=C4)F |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC1=C(C=C(C=C1)[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)CC3=CC=C(S3)C4=CC=C(C=C4)F |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C24H25FO5S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID601004469 |
Source
|
| Record name | Canagliflozin | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID601004469 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
444.5 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Boiling Point |
642.9±55.0 |
Source
|
| Record name | Canagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08907 | |
| 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) | |
Solubility |
almost insoluble, Practically insoluble in aqueous media from pH 1.1 to pH 12.9 /Canagliflozin hemihydrate/ |
Source
|
| Record name | Canagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08907 | |
| 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 | Canagliflozin | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8284 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Mechanism of Action |
The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine., Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE). |
Source
|
| Record name | Canagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08907 | |
| 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 | Canagliflozin | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8284 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
842133-18-0 |
Source
|
| Record name | Canagliflozin | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=842133-18-0 | |
| 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 | Canagliflozin | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0842133180 | |
| 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 | Canagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08907 | |
| 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 | Canagliflozin | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID601004469 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | (1S)-1,5-Anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl]}-4-methylphenyl)-D-glucitol | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| 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 | CANAGLIFLOZIN ANHYDROUS | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/6S49DGR869 | |
| 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 | Canagliflozin | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8284 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Melting Point |
68-72 |
Source
|
| Record name | Canagliflozin | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB08907 | |
| 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) | |
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
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