Legend: drug field target field enzyme field
| Version | 2.5 | ||||
| Creation Date | 2005-06-13 13:24:05 | ||||
| Update Date | 2009-02-19 16:05:06 | ||||
| Primary Accession Number | DB00412 | ||||
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| Name | Rosiglitazone | ||||
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| 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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| Chemical IUPAC Name | 5-[[4-[2-(methyl-pyridin-2-ylamino)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione | ||||
| Chemical Formula | C18H19N3O3S | ||||
| Chemical Structure | |||||
| CAS Registry Number | 122320-73-4 | ||||
| InChI Identifier | InChI=1/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)/f/h20H | ||||
| InChI Key | YASAKCUCGLMORW-UYBDAZJACF | ||||
| KEGG Drug | D00596 ![]() |
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| KEGG Compound | Not Available | ||||
| PubChem Compound | 77999 ![]() |
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| PubChem Substance | 7980539 ![]() |
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| ChEBI ID | Not Available | ||||
| PharmGKB ID | PA451283 ![]() |
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| HET ID | BRL ![]() |
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| GenBank ID | Not Available | ||||
| Drug ID Number [DIN] | 02241113 ![]() |
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| RxList Link | http://www.rxlist.com/cgi/generic2/rosigl.htm ![]() |
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| PDRhealth Link | http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cx1532.shtml ![]() |
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| Wikipedia Link | http://en.wikipedia.org/wiki/Rosiglitazone ![]() |
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| FDA Label |
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| Material Safety Data Sheet (MSDS) | |||||
| Synthesis Reference | Crowther, Smith, U.S. Pat. 3,337,628 (1967) | ||||
| Average Molecular Weight | 357.4270 | ||||
| Monoisotopic Molecular Weight | 357.1147 | ||||
| State | Solid | ||||
| Melting Point | 122-123 oC | ||||
| Experimental Water Solubility | Not Available Source: PhysProp | ||||
| Predicted Water Solubility | 3.80e-02 mg/mL Calculated using ALOGPS | ||||
| Experimental LogP/Hydrophobicity | 2.4 Source: PhysProp | ||||
| Predicted LogP | 2.95 Calculated using ALOGPS | ||||
| Experimental LogS | Not Available | ||||
| Predicted LogS | -3.97 Calculated using ALOGPS | ||||
| Experimental Caco2 Permeability | Not Available | ||||
| pKa/Isoelectric Point | Not Available | ||||
| Mass Spectrum | Not Available | ||||
| MOL File | Show | Download ![]() |
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| SDF File | Show | Download ![]() |
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| PDB File | Show | Download ![]() |
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| 2D Structure | |||||
| 3D Structure | |||||
| Experimental PDB ID | Not Available | ||||
| Isomeric SMILES | CN(CCOC1=CC=C(C[C@H]2SC(=O)NC2=O)C=C1)C1=CC=CC=N1 | ||||
| Canonical SMILES | CN(CCOC1=CC=C(CC2SC(=O)NC2=O)C=C1)C1=CC=CC=N1 | ||||
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| Indication | For the treatment of Type II diabetes mellitus | ||||
| Pharmacology | 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. | ||||
| Toxicity | Side effects include fluid retention, congestive heart failure (CHF), liver disease | ||||
| Protein Binding | 99.8% bound to plasma proteins, primarily albumin. | ||||
| Biotransformation | 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. | ||||
| Half Life | 3-4 hours | ||||
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| Patient Information | Show ![]() |
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| Contraindications | Show ![]() |
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| Interactions | Show ![]() |
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| Drug Interactions | Not Available | ||||
| Food Interactions | Not Available | ||||
| Pathways | Not Available | ||||
| General References |
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| Organisms Affected |
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| Phase 1 Metabolizing Enzymes | |||||
| Targets |
| Phase 1 Metabolizing Enzyme 1 [top] | |
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| Enzyme 1 Name | Cytochrome P450 2C8 (CYP2C8) |
| Enzyme 1 Gene Name | CYP2C8 |
| Enzyme 1 SwissProt ID | P10632 ![]() |
| Enzyme 1 SNPs | SNPJam Report ![]() |
| Enzyme 1 Protein Sequence |
>sp|P10632|CP2C8_HUMAN Cytochrome P450 2C8 (EC 1.14.14.1)
MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKV YGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRW KEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICS VVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALT RSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTE TTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSD LVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFK KSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLP PSYQICFIPV |
| Phase 1 Metabolizing Enzyme 2 [top] | |
| Enzyme 2 Name | Cytochrome P450 2C9 (CYP2C9) |
| Enzyme 2 Gene Name | CYP2C9 |
| Enzyme 2 SwissProt ID | P11712 ![]() |
| Enzyme 2 SNPs | SNPJam Report ![]() |
| Enzyme 2 Protein Sequence |
>sp|P11712|CP2C9_HUMAN Cytochrome P450 2C9 (EC 1.14.13.80)
MDSLVVLVLCLSCLLLLSLWRQSSGRGKLPPGPTPLPVIGNILQIGIKDISKSLTNLSKV YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKW KEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICS IIFHKRFDYKDQQFLNLMEKLNENIKILSSPWIQICNNFSPIIDYFPGTHNKLLKNVAFM KSYILEKVKEHQESMDMNNPQDFIDCFLMKMEKEKHNQPSEFTIESLENTAVDLFGAGTE TTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRSHMPYTDAVVHEVQRYID LLPTSLPHAVTCDIKFRNYLIPKGTTILISLTSVLHDNKEFPNPEMFDPHHFLDEGGNFK KSKYFMPFSAGKRICVGEALAGMELFLFLTSILQNFNLKSLVDPKNLDTTPVVNGFASVP PFYQLCFIPV |
| Drug Target 1 [top] | |||||||
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| Target 1 ID | 238 | ||||||
| Target 1 Name | Peroxisome proliferator-activated receptor gamma | ||||||
| Target 1 Synonyms |
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| Target 1 Gene Name | PPARG | ||||||
| Target 1 Protein Sequence |
>Peroxisome proliferator-activated receptor gamma
MGETLGDSPIDPESDSFTDTLSANISQEMTMVDTEMPFWPTNFGISSVDLSVMEDHSHSF DIKPFTTVDFSSISTPHYEDIPFTRTDPVVADYKYDLKLQEYQSAIKVEPASPPYYSEKT QLYNKPHEEPSNSLMAIECRVCGDKASGFHYGVHACEGCKGFFRRTIRLKLIYDRCDLNC RIHKKSRNKCQYCRFQKCLAVGMSHNAIRFGRMPQAEKEKLLAEISSDIDQLNPESADLR ALAKHLYDSYIKSFPLTKAKARAILTGKTTDKSPFVIYDMNSLMMGEDKIKFKHITPLQE QSKEVAIRIFQGCQFRSVEAVQEITEYAKSIPGFVNLDLNDQVTLLKYGVHEIIYTMLAS LMNKDGVLISEGQGFMTREFLKSLRKPFGDFMEPKFEFAVKFNALELDDSDLAIFIAVII LSGDRPGLLNVKPIEDIQDNLLQALELQLKLNHPESSQLFAKLLQKMTDLRQIVTEHVQL LQVIKKTETDMSLHPLLQEIYKDLY |
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| Target 1 Number of Residues | 513 | ||||||
| Target 1 Molecular Weight | 57621 | ||||||
| Target 1 Theoretical pI | 5.77 | ||||||
| Target 1 GO Classification |
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| Target 1 General Function | Involved in DNA binding | ||||||
| Target 1 Specific Function | 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 | ||||||
| Target 1 Pathways | Not Available | ||||||
| Target 1 Reactions | Not Available | ||||||
| Target 1 Pfam Domain Function | |||||||
| Target 1 Signals |
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| Target 1 Transmembrane Regions |
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| Target 1 Essentiality | Non-Essential | ||||||
| Target 1 GenBank ID Protein | 1711117 ![]() |
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| Target 1 UniProtKB/Swiss-Prot ID | P37231 ![]() |
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| Target 1 UniProtKB/Swiss-Prot Entry Name | PPARG_HUMAN ![]() |
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| Target 1 PDB ID | 1I7I ![]() |
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| Target 1 PDB File | Show | ||||||
| Target 1 3D Structure | |||||||
| Target 1 Cellular Location |
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| Target 1 Gene Sequence |
>1518 bp
ATGGGTGAAACTCTGGGAGATTCTCCTATTGACCCAGAAAGCGATTCCTTCACTGATACA CTGTCTGCAAACATATCACAAGAAATGACCATGGTTGACACAGAGATGCCATTCTGGCCC ACCAACTTTGGGATCAGCTCCGTGGATCTCTCCGTAATGGAAGACCACTCCCACTCCTTT GATATCAAGCCCTTCACTACTGTTGACTTCTCCAGCATTTCTACTCCACATTACGAAGAC ATTCCATTCACAAGAACAGATCCAGTGGTTGCAGATTACAAGTATGACCTGAAACTTCAA GAGTACCAAAGTGCAATCAAAGTGGAGCCTGCATCTCCACCTTATTATTCTGAGAAGACT CAGCTCTACAATAAGCCTCATGAAGAGCCTTCCAACTCCCTCATGGCAATTGAATGTCGT GTCTGTGGAGATAAAGCTTCTGGATTTCACTATGGAGTTCATGCTTGTGAAGGATGCAAG GGTTTCTTCCGGAGAACAATCAGATTGAAGCTTATCTATGACAGATGTGATCTTAACTGT CGGATCCACAAAAAAAGTAGAAATAAATGTCAGTACTGTCGGTTTCAGAAATGCCTTGCA GTGGGGATGTCTCATAATGCCATCAGGTTTGGGCGGATGCCACAGGCCGAGAAGGAGAAG CTGTTGGCGGAGATCTCCAGTGATATCGACCAGCTGAATCCAGAGTCCGCTGACCTCCGG GCCCTGGCAAAACATTTGTATGACTCATACATAAAGTCCTTCCCGCTGACCAAAGCAAAG GCGAGGGCGATCTTGACAGGAAAGACAACAGACAAATCACCATTCGTTATCTATGACATG AATTCCTTAATGATGGGAGAAGATAAAATCAAGTTCAAACACATCACCCCCCTGCAGGAG CAGAGCAAAGAGGTGGCCATCCGCATCTTTCAGGGCTGCCAGTTTCGCTCCGTGGAGGCT GTGCAGGAGATCACAGAGTATGCCAAAAGCATTCCTGGTTTTGTAAATCTTGACTTGAAC GACCAAGTAACTCTCCTCAAATATGGAGTCCACGAGATCATTTACACAATGCTGGCCTCC TTGATGAATAAAGATGGGGTTCTCATATCCGAGGGCCAAGGCTTCATGACAAGGGAGTTT CTAAAGAGCCTGCGAAAGCCTTTTGGTGACTTTATGGAGCCCAAGTTTGAGTTTGCTGTG AAGTTCAATGCACTGGAATTAGATGACAGCGACTTGGCAATATTTATTGCTGTCATTATT CTCAGTGGAGACCGCCCAGGTTTGCTGAATGTGAAGCCCATTGAAGACATTCAAGACAAC CTGCTACAAGCCCTGGAGCTCCAGCTGAAGCTGAACCACCCTGAGTCCTCACAGCTGTTT GCCAAGCTGCTCCAGAAAATGACAGACCTCAGACAGATTGTCACGGAACACGTGCAGCTA CTGCAGGTGATCAAGAAGACGGAGACAGACATGAGTCTTCACCCGCTCCTGCAGGAGATC TACAAGGACTTGTACTAG |
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| Target 1 GenBank Gene ID | |||||||
| Target 1 GeneCard ID | PPARG ![]() |
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| Target 1 GenAtlas ID | PPARG ![]() |
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| Target 1 HGNC ID | HGNC:9236 ![]() |
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| Target 1 Chromosome Location | 3 | ||||||
| Target 1 Locus | 3p25 | ||||||
| Target 1 SNPs | SNPJam Report ![]() |
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| Target 1 General References |
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| Target 1 Drug References |
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This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.