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| Name | Rosiglitazone | ||||||||||||||||||||||||||||||||||||||||||
| Accession Number | DB00412 (APRD00403) | ||||||||||||||||||||||||||||||||||||||||||
| Type | small molecule | ||||||||||||||||||||||||||||||||||||||||||
| Groups | approved | ||||||||||||||||||||||||||||||||||||||||||
| Description | Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl). Like other thiazolidinediones, the mechanism of action of rosiglitazone is by activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPARγ. Rosiglitazone is a selective ligand of PPARγ, and has no PPARα-binding action. Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB) levels increase in patients on rosiglitazone. Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer’s disease not expressing the ApoE4 allele. This is the subject of a clinical trial currently underway. |
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| Structure |
Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure |
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| Salts | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| CAS number | 122320-73-4 | ||||||||||||||||||||||||||||||||||||||||||
| Weight |
Average: 357.427 Monoisotopic: 357.114712179 |
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| Chemical Formula | C18H19N3O3S | ||||||||||||||||||||||||||||||||||||||||||
| InChI Key | InChIKey=YASAKCUCGLMORW-UHFFFAOYSA-N | ||||||||||||||||||||||||||||||||||||||||||
| InChI |
InChI=1S/C18H19N3O3S/c1-21(16-4-2-3-9-19-16)10-11-24-14-7-5-13(6-8-14)12-15-17(22)20-18(23)25-15/h2-9,15H,10-12H2,1H3,(H,20,22,23)
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| IUPAC Name |
5-[(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}phenyl)methyl]-1,3-thiazolidine-2,4-dione
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| SMILES |
CN(CCOC1=CC=C(CC2SC(=O)NC2=O)C=C1)C1=CC=CC=N1
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| Mass Spec | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Taxonomy | |||||||||||||||||||||||||||||||||||||||||||
| Kingdom | Organic | ||||||||||||||||||||||||||||||||||||||||||
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| Pharmacology | |||||||||||||||||||||||||||||||||||||||||||
| Indication | For the treatment of Type II diabetes mellitus | ||||||||||||||||||||||||||||||||||||||||||
| Pharmacodynamics | Rosiglitazone, a member of the drug group known as the thiazolidinediones or "insulin sensitizers", is not chemically or functionally related to the alpha-glucosidase inhibitors, the biguanides, or the sulfonylureas. Rosiglitazone targets insulin resistance and, hence, is used alone or with metformine or sulfonylurea to improve glycemic control in patients with type 2 diabetes mellitus. | ||||||||||||||||||||||||||||||||||||||||||
| Mechanism of action | Rosiglitazone acts as an agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin. | ||||||||||||||||||||||||||||||||||||||||||
| Absorption | The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. | ||||||||||||||||||||||||||||||||||||||||||
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| Protein binding | 99.8% bound to plasma proteins, primarily albumin. | ||||||||||||||||||||||||||||||||||||||||||
| Metabolism | Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone. | ||||||||||||||||||||||||||||||||||||||||||
| Route of elimination | Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. | ||||||||||||||||||||||||||||||||||||||||||
| Half life | 3-4 hours | ||||||||||||||||||||||||||||||||||||||||||
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| Toxicity | Side effects include fluid retention, congestive heart failure (CHF), liver disease | ||||||||||||||||||||||||||||||||||||||||||
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| Pathways | Not Available | ||||||||||||||||||||||||||||||||||||||||||
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| Prices |
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational
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| Properties | |||||||||||||||||||||||||||||||||||||||||||
| State | solid | ||||||||||||||||||||||||||||||||||||||||||
| Experimental Properties |
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| Synthesis Reference | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| General Reference |
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| PDB Entries | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| FDA label | show (86.2 KB) | ||||||||||||||||||||||||||||||||||||||||||
| MSDS | show (30 KB) | ||||||||||||||||||||||||||||||||||||||||||
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| Drug Interactions |
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| Food Interactions | Not Available | ||||||||||||||||||||||||||||||||||||||||||
| Targets |
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1. Peroxisome proliferator-activated receptor gamma Pharmacological action: yesActions: agonist Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis Organism class: humanUniProt ID: P37231 ![]() Gene: PPARG ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
2. Long-chain-fatty-acid--CoA ligase 4 Pharmacological action: unknownActions: inhibitor Activation of long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Preferentially uses arachidonate and eicosapentaenoate as substrates Organism class: humanUniProt ID: O60488 ![]() Gene: ACSL4 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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| Enzymes |
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Actions: substrate, inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol) UniProt ID: P10632![]() Gene: CYP2C8 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: substrate, inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan UniProt ID: P11712![]() Gene: CYP2C9 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
3. Prostaglandin G/H synthase 1 Actions: substrateMay play an important role in regulating or promoting cell proliferation in some normal and neoplastically transformed cells UniProt ID: P23219![]() Gene: PTGS1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen UniProt ID: P05177![]() Gene: CYP1A2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase UniProt ID: P11509![]() Gene: CYP2A6 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine UniProt ID: P33261![]() Gene: CYP2C19 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
Actions: inhibitor
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants UniProt ID: P10635![]() Gene: CYP2D6 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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| Transporters |
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1. Solute carrier organic anion transporter family member 1B1 Actions: inhibitorMediates the Na(+)-independent transport of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. May play an important role in the clearance of bile acids and organic anions from the liver UniProt ID: Q9Y6L6![]() Gene: SLCO1B1 ![]() Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report ![]() References:
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