カナグリフロジン
概要
説明
カナグリフロジンは、主に2型糖尿病の治療に使用される薬剤です。 これは、ナトリウム-グルコース共輸送体2（SGLT2）阻害剤のクラスに属し、腎臓でのグルコースの再吸収を阻害することで、尿中へのグルコース排泄を増加させることで作用します 。このメカニズムは、2型糖尿病患者の血糖値を下げるのに役立ちます。 カナグリフロジンは、2013年に米国、欧州連合、オーストラリアで医療用として承認されました .
2. 製法
合成経路と反応条件： カナグリフロジンの合成には、鍵となる中間体の調製から始まる複数のステップが含まれます。 その方法の1つは、水または混合溶媒中のカナグリフロジンの懸濁系を形成し、その後結晶化することです 。 もう1つの方法は、テトラヒドロフランやメタノールなどの溶媒に中間体を溶解させ、塩酸を用いて加水分解することです .
工業生産方法： カナグリフロジンの工業生産には、一般的に化合物の溶解度とバイオアベイラビリティの最適化が含まれます。 マイクロエマルジョンプレコンセントレートなどの技術が、カナグリフロジンの溶解度と経口バイオアベイラビリティを向上させるために使用されています 。最適化された製剤は、その溶解速度、透過速度、および経口バイオアベイラビリティについて評価されます。
作用機序
カナグリフロジンは、腎臓の近位尿細管におけるナトリウム-グルコース共輸送体2（SGLT2）を阻害することでその効果を発揮します 。 この阻害は、腎臓尿細管腔からのグルコースの再吸収を阻止し、尿中へのグルコース排泄の増加につながります 。 このメカニズムに関与する分子標的には、腎臓でのグルコース再吸収に関与するSGLT2タンパク質が含まれます .
類似化合物：
- ダパグリフロジン
- エンパグリフロジン
- メトホルミン
- オゼンピック（セマグルチド）
比較：
科学的研究の応用
Canagliflozin has a wide range of scientific research applications:
生化学分析
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
Canagliflozin 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 Canagliflozin 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 Canagliflozin on intestinal flora and metabolites have been studied in diabetic mice over a period of 8 weeks . It was found that Canagliflozin significantly increased GLP-1 level and impacted on the composition of gut microbiota and metabolites .
Metabolic Pathways
Canagliflozin influences intestinal fatty acid and bile acid (BA) metabolism . It increases fatty acids metabolites in feces .
準備方法
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 canagliflozin 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 canagliflozin 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 canagliflozin . The optimized formulation is evaluated for its dissolution rate, permeation rate, and oral bioavailability.
化学反応の分析
反応の種類： カナグリフロジンは、酸化やグルクロン酸抱合など、さまざまな化学反応を受けます。 主要な代謝経路には、O-グルクロン酸抱合代謝物の形成と酸化生成物の形成が含まれます .
一般的な試薬と条件：
酸化： カナグリフロジンは、M8やM9などの代謝物を生成するために酸化される可能性があります.
グルクロン酸抱合： この反応には、カナグリフロジンへのグルクロン酸の付加が含まれ、M5、M7、M17などの代謝物を生成します.
主要な生成物： これらの反応から生成される主要な生成物には、O-グルクロン酸抱合代謝物と酸化生成物が含まれ、これらは体から排泄されます .
4. 科学研究への応用
カナグリフロジンは、幅広い科学研究への応用があります。
類似化合物との比較
- Dapagliflozin
- Empagliflozin
- Metformin
- Ozempic (semaglutide)
Comparison:
- Efficacy: Canagliflozin has been shown to have similar efficacy in lowering HbA1c levels compared to empagliflozin and dapagliflozin . canagliflozin may have a slightly higher efficacy at lowering HbA1c compared to dapagliflozin .
- Safety: The safety profiles of canagliflozin, dapagliflozin, and empagliflozin are comparable, with common side effects including urinary tract infections and genital infections .
- Uniqueness: Canagliflozin is unique in its ability to reduce brain swelling in cerebral ischemia, a property not commonly associated with other SGLT2 inhibitors .
特性
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
試験管内研究製品の免責事項と情報
BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。
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