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Record Information
Version2.0
Creation Date2014-09-11 05:16:39 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4789
Identification
Common NameTroglitazone
ClassSmall Molecule
DescriptionTroglitazone was withdrawn in 2000 due to risk of hepatotoxicity. It was superseded by pioglitazone and rosiglitazone.
Compound Type
  • Amide
  • Amine
  • Drug
  • Ether
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Noscal
Resulin
Rezulin
Romozin
Chemical FormulaC24H27NO5S
Average Molecular Mass441.540 g/mol
Monoisotopic Mass441.161 g/mol
CAS Registry Number97322-87-7
IUPAC Name5-({4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-1-benzopyran-2-yl)methoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione
Traditional Nametroglitazone
SMILESCC1=C(O)C(C)=C2CCC(C)(COC3=CC=C(CC4SC(=O)N=C4O)C=C3)OC2=C1C
InChI IdentifierInChI=1/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)
InChI KeyInChIKey=GXPHKUHSUJUWKP-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as 1-benzopyrans. These are organic aromatic compounds that 1-benzopyran, a bicyclic compound made up of a benzene ring fused to a pyran, so that the oxygen atom is at the 1-position.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzopyrans
Sub Class1-benzopyrans
Direct Parent1-benzopyrans
Alternative Parents
Substituents
  • 1-benzopyran
  • Phenoxy compound
  • Phenol ether
  • Alkyl aryl ether
  • Thiazolidinedione
  • Monocyclic benzene moiety
  • Benzenoid
  • Dicarboximide
  • Thiazolidine
  • Carbonic acid derivative
  • Thiocarbamic acid derivative
  • Carboxylic acid derivative
  • Ether
  • Oxacycle
  • Azacycle
  • Organonitrogen compound
  • Organic oxide
  • Organopnictogen compound
  • Organic nitrogen compound
  • Organooxygen compound
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Carbonyl group
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point184-186°C
Boiling PointNot Available
SolubilityNot Available
LogP3.6
Predicted Properties
PropertyValueSource
Water Solubility0.0012 g/LALOGPS
logP4.16ALOGPS
logP5.5ChemAxon
logS-5.6ALOGPS
pKa (Strongest Acidic)6.61ChemAxon
pKa (Strongest Basic)-4.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area84.86 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity120.99 m³·mol⁻¹ChemAxon
Polarizability47.08 ųChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a6r-1889600000-e7d440741c30fa701997JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TBDMS_1_2) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - 60V, Negativesplash10-0f6t-1900000000-b41d1d9b00383779a8beJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 45V, Negativesplash10-0f6t-0900000000-ab7c5539034df635ac14JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 75V, Negativesplash10-0fr2-1900000000-1a1e22916ed5413720ebJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 90V, Negativesplash10-014j-2900000000-52697cbd413c9fbe49f8JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Negativesplash10-0005-1507900000-4f7d34b5dc4e0c481b68JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 15V, Negativesplash10-0006-0000900000-8c86a1f2bb9af73c4ae9JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 60V, Positivesplash10-014i-1900000000-c7a1ca757fec1b1a4e5eJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 75V, Positivesplash10-014i-3900000000-c72fbe14217a1770ef4dJSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-0430900000-ceb18bd79d0f6da79e7dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014i-0912100000-c1ddd0b2276cc0642c28JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0bt9-0910000000-70eed845667711a7ff74JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0133900000-d4c360adbc610d5363cfJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0v4l-4759300000-7eda5e5df7869dbcd569JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9700000000-bbf919843d75c50ea813JSpectraViewer
Toxicity Profile
Route of ExposureAbsorbed rapidly. Food increases the extent of absorption by 30% to 85%.
Mechanism of ToxicityTroglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Troglitazone is a ligand to both PPAR‘± and PPAR‘_, with a highter affinity for PPAR‘_. The drug also contains an ‘±-tocopheroyl moiety, potentially giving it vitamin E-like activity. Troglitazone has been shown to reduce inflammation, and is associated with a decrase in nuclear factor kappa-B (NF-‘_B) and a concomitant increase in its inhibitor (I‘_B). NF-‘_B is an important cellular transcription regulator for the immune response. Unlike sulfonylureas, troglitazone is not an insulin secretagogue.
MetabolismA sulfate conjugate metabolite (Metabolite 1) and a quinone metabolite (Metabolite 3) have been detected in the plasma of healthy males. A glucuronide conjugate (Metabolite 2) has been detected in the urine and also in negligible amounts in the plasma. In healthy volunteers and in patients with type 2 diabetes, the steady-state concentration of Metabolite 1 is six to seven times that of troglitazone and Metabolite 3. In in vivo drug interaction studies, troglitazone has been shown to induce cytochrome P450 CYP3A4 at clinically relevant doses. Half Life: 16-34 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of Type II diabetes mellitus. It is used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00197
HMDB IDNot Available
PubChem Compound ID5591
ChEMBL IDNot Available
ChemSpider ID5389
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID9753
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkTroglitazone
References
Synthesis Reference

Krishnamurthi Vyas, Chebiyyam Prabhakar, Sreenivas Dharmaraja Rao, Mamillapalli Ramabadhra Sarma, Om Gaddam Reddy, Rajagopalan Ramanujam, Ranjan Chakrabarti, “Polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation.” U.S. Patent US5700820, issued June, 1992.

MSDST3D4789.pdf
General References
  1. Aljada A, Garg R, Ghanim H, Mohanty P, Hamouda W, Assian E, Dandona P: Nuclear factor-kappaB suppressive and inhibitor-kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes: evidence of an antiinflammatory action? J Clin Endocrinol Metab. 2001 Jul;86(7):3250-6. [11443197 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Serine-type endopeptidase inhibitor activity
Specific Function:
Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis.
Gene Name:
SERPINE1
Uniprot ID:
P05121
Molecular Weight:
45059.695 Da
References
  1. Sobel BE: Insulin resistance and thrombosis: a cardiologist's view. Am J Cardiol. 1999 Jul 8;84(1A):37J-41J. [10418858 ]
  2. Gottschling-Zeller H, Rohrig K, Hauner H: Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. Diabetologia. 2000 Mar;43(3):377-83. [10768100 ]
  3. Nordt TK, Peter K, Bode C, Sobel BE: Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells. J Clin Endocrinol Metab. 2000 Apr;85(4):1563-8. [10770198 ]
  4. Kato K, Yamada D, Midorikawa S, Sato W, Watanabe T: Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus. Metabolism. 2000 May;49(5):662-5. [10831180 ]
  5. Kruszynska YT, Yu JG, Olefsky JM, Sobel BE: Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes. 2000 Apr;49(4):633-9. [10871202 ]
General Function:
Very long-chain fatty acid-coa ligase activity
Specific Function:
Activation of long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Preferentially uses arachidonate and eicosapentaenoate as substrates.
Gene Name:
ACSL4
Uniprot ID:
O60488
Molecular Weight:
79187.38 Da
References
  1. Kim JH, Lewin TM, Coleman RA: Expression and characterization of recombinant rat Acyl-CoA synthetases 1, 4, and 5. Selective inhibition by triacsin C and thiazolidinediones. J Biol Chem. 2001 Jul 6;276(27):24667-73. Epub 2001 Apr 23. [11319222 ]
  2. Lewin TM, Van Horn CG, Krisans SK, Coleman RA: Rat liver acyl-CoA synthetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes, and mitochondrial-associated membrane. Arch Biochem Biophys. 2002 Aug 15;404(2):263-70. [12147264 ]
  3. Lewin TM, Kim JH, Granger DA, Vance JE, Coleman RA: Acyl-CoA synthetase isoforms 1, 4, and 5 are present in different subcellular membranes in rat liver and can be inhibited independently. J Biol Chem. 2001 Jul 6;276(27):24674-9. Epub 2001 Apr 23. [11319232 ]
General Function:
Nucleoside transmembrane transporter activity
Specific Function:
Mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs).
Gene Name:
SLC29A1
Uniprot ID:
Q99808
Molecular Weight:
50218.805 Da
References
  1. Leung GP, Man RY, Tse CM: Effect of thiazolidinediones on equilibrative nucleoside transporter-1 in human aortic smooth muscle cells. Biochem Pharmacol. 2005 Aug 1;70(3):355-62. [15963471 ]
General Function:
Zinc ion binding
Specific Function:
Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity). Induces the expression of PERM1 in the skeletal muscle.
Gene Name:
ESRRG
Uniprot ID:
P62508
Molecular Weight:
51305.485 Da
References
  1. Wang Y, Fang F, Wong CW: Troglitazone is an estrogen-related receptor alpha and gamma inverse agonist. Biochem Pharmacol. 2010 Jul 1;80(1):80-5. doi: 10.1016/j.bcp.2010.03.013. Epub 2010 Mar 16. [20298676 ]
General Function:
Zinc ion binding
Specific Function:
Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle.
Gene Name:
ESRRA
Uniprot ID:
P11474
Molecular Weight:
45509.11 Da
References
  1. Wang Y, Fang F, Wong CW: Troglitazone is an estrogen-related receptor alpha and gamma inverse agonist. Biochem Pharmacol. 2010 Jul 1;80(1):80-5. doi: 10.1016/j.bcp.2010.03.013. Epub 2010 Mar 16. [20298676 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).
Gene Name:
PPARG
Uniprot ID:
P37231
Molecular Weight:
57619.58 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.322 uMATG_PPARg_TRANSAttagene
AC500.412 uMNVS_NR_hPPARgNovascreen
AC500.0347 uMTox21_PPARg_BLA_Agonist_ratioTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.
Gene Name:
PPARA
Uniprot ID:
Q07869
Molecular Weight:
52224.595 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.147 uMATG_PPRE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:
NR1I2
Uniprot ID:
O75469
Molecular Weight:
49761.245 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC503.16 uMATG_PXR_TRANSAttagene
AC502.73 uMATG_PXRE_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Zinc ion binding
Specific Function:
Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.
Gene Name:
NR1H4
Uniprot ID:
Q96RI1
Molecular Weight:
55913.915 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.67 uMOT_SRC1_SRC1FXR_1440Odyssey Thera
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Transcriptional activator activity, rna polymerase ii core promoter proximal region sequence-specific binding
Specific Function:
Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor. In the heterodimer, FOS and JUN/AP-1 basic regions each seems to interact with symmetrical DNA half sites. On TGF-beta activation, forms a multimeric SMAD3/SMAD4/JUN/FOS complex at the AP1/SMAD-binding site to regulate TGF-beta-mediated signaling. Has a critical function in regulating the development of cells destined to form and maintain the skeleton. It is thought to have an important role in signal transduction, cell proliferation and differentiation. In growing cells, activates phospholipid synthesis, possibly by activating CDS1 and PI4K2A. This activity requires Tyr-dephosphorylation and association with the endoplasmic reticulum.
Gene Name:
FOS
Uniprot ID:
P01100
Molecular Weight:
40694.855 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC509.03 uMATG_AP_1_CISAttagene
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]