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Record Information
Version2.0
Creation Date2014-10-14 21:18:37 UTC
Update Date2014-12-24 20:27:01 UTC
Accession NumberT3D4981
Identification
Common NamePioglitazone
ClassSmall Molecule
DescriptionPioglitazone is used for the treatment of diabetes mellitus type 2. Pioglitazone selectively stimulates nuclear receptor peroxisone proliferator-activated receptor gamma (PPAR-gamma). It modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the lipidic, muscular tissues and in the liver.
Compound Type
  • Drug
  • Hypoglycemic Agent
  • Metabolite
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(+-)-5-((4-(2-(5-Ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-2,4-thiazolidinedione
Actos
Actost
Glustin
Pioglitazona
Pioglitazone HCl
Pioglitazone Hydrochloride
Pioglitazonum
Chemical FormulaC19H20N2O3S
Average Molecular Mass356.439 g/mol
Monoisotopic Mass356.119 g/mol
CAS Registry Number111025-46-8
IUPAC Name5-({4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione
Traditional Namepioglitazone
SMILESCCC1=CN=C(CCOC2=CC=C(CC3SC(=O)N=C3O)C=C2)C=C1
InChI IdentifierInChI=1/C19H20N2O3S/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23)
InChI KeyInChIKey=HYAFETHFCAUJAY-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenol ethers
Sub ClassNot Available
Direct ParentPhenol ethers
Alternative Parents
Substituents
  • Phenoxy compound
  • Phenol ether
  • Alkyl aryl ether
  • Thiazolidinedione
  • Monocyclic benzene moiety
  • Pyridine
  • Dicarboximide
  • Heteroaromatic compound
  • Thiazolidine
  • Carbonic acid derivative
  • Thiocarbamic acid derivative
  • Carboxylic acid derivative
  • Ether
  • Azacycle
  • Organoheterocyclic compound
  • Organonitrogen compound
  • Organic oxide
  • Organopnictogen compound
  • Organic nitrogen compound
  • Organooxygen compound
  • Hydrocarbon derivative
  • Organic oxygen compound
  • Carbonyl group
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceNot Available
Experimental Properties
PropertyValue
Melting Point183-184 °C
Boiling PointNot Available
Solubilitymg/mL
LogP2.3
Predicted Properties
PropertyValueSource
Water Solubility0.0044 g/LALOGPS
logP3.17ALOGPS
logP3.33ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)6.66ChemAxon
pKa (Strongest Basic)5.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area68.29 ŲChemAxon
Rotatable Bond Count7ChemAxon
Refractivity97.39 m³·mol⁻¹ChemAxon
Polarizability37.91 ųChemAxon
Number of Rings3ChemAxon
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, Positivesplash10-05fr-0982000000-bc531fd621e090712033JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a4i-0009000000-070cf69939743719671dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0bt9-0209000000-d9d34be41f49a9ffbdefJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0udi-0900000000-ef25b6f93ae4fcee23c3JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0udi-0900000000-3011f00e839bfc06d89dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0gba-0900000000-b0488e0d155d1587bbb5JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-014j-0900000000-b32570ad6af58a4a6c72JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0a4i-0009000000-c67370f6cb2ad36cab3eJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QTOF , positivesplash10-0a59-0908000000-aab2ee9addb1334a7064JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0a4i-0009000000-fd4bc4d9d4bb45e91295JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0a4i-0409000000-115c6889c4e9205b3028JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-001i-0900000000-a2e878da4d2f6a4bb717JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-001i-0900000000-031fa259cd3b26217dadJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-00lr-0900000000-e2cd3c294a2e53e1a17eJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0159-1900000000-aacbd8dce006b5ef5938JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-1619000000-4b248e31af7f50e87108JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-053r-0906000000-a73152b364036b45dfebJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 45V, Negativesplash10-0udi-0900000000-4cbb6d60c5b330f46e83JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 30V, Negativesplash10-0bt9-0009000000-e15320a688303951fc88JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 60V, Negativesplash10-0udi-0900000000-83eb5dacf9c310e76b61JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0219000000-989038e0dc6e9a9ecf80JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0540-0984000000-b1e6f3241976f6936760JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0kai-1900000000-8b2d810f6330f368aa47JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0159000000-0b74a48747ffb1b4f2d2JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0uec-3692000000-141c6eb446379ead16bbJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0f6x-9700000000-a10d6ccf2ad58937dfa5JSpectraViewer
Toxicity Profile
Route of ExposureFollowing oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
Mechanism of ToxicityPioglitazone 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 increases the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, pioglitazone both enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis. Thus, insulin resistance associated with type 2 diabetes mellitus is improved without an increase in insulin secretion by pancreatic β cells.
MetabolismHepatic
Toxicity ValuesHypogycemia; LD50=mg/kg (orally in rat)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)2A, probably carcinogenic to humans. (4)
Uses/SourcesTreatment of Type II diabetes mellitus
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01132
HMDB IDHMDB15264
PubChem Compound ID4829
ChEMBL IDCHEMBL595
ChemSpider ID4663
KEGG IDC07675
UniProt IDNot Available
OMIM ID
ChEBI ID8228
BioCyc IDNot Available
CTD IDC060836
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkPioglitazone
References
Synthesis Reference

Chandra Khanduri, Yatendra Kumar, Atulya Panda, Suchitra Chakraborty, Mukesh Sharma, “Process for the preparation of pioglitazone.” U.S. Patent US20070078170, issued April 05, 2007.

MSDST3D4981.pdf
General References
  1. Colca JR, McDonald WG, Waldon DJ, Leone JW, Lull JM, Bannow CA, Lund ET, Mathews WR: Identification of a novel mitochondrial protein ("mitoNEET") cross-linked specifically by a thiazolidinedione photoprobe. Am J Physiol Endocrinol Metab. 2004 Feb;286(2):E252-60. Epub 2003 Oct 21. [14570702 ]
  2. Paddock ML, Wiley SE, Axelrod HL, Cohen AE, Roy M, Abresch EC, Capraro D, Murphy AN, Nechushtai R, Dixon JE, Jennings PA: MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14342-7. Epub 2007 Aug 31. [17766440 ]
  3. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE: Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007 Sep 12;298(10):1180-8. [17848652 ]
  4. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

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
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Sugii S, Olson P, Sears DD, Saberi M, Atkins AR, Barish GD, Hong SH, Castro GL, Yin YQ, Nelson MC, Hsiao G, Greaves DR, Downes M, Yu RT, Olefsky JM, Evans RM: PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22504-9. doi: 10.1073/pnas.0912487106. Epub 2009 Dec 16. [20018750 ]
  3. Miyazaki Y, Mahankali A, Wajcberg E, Bajaj M, Mandarino LJ, DeFronzo RA: Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2004 Sep;89(9):4312-9. [15356026 ]
  4. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953-6. [7768881 ]
  5. Spiegelman BM: PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998 Apr;47(4):507-14. [9568680 ]
  6. Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM: The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones. J Med Chem. 1996 Feb 2;39(3):665-8. [8576907 ]
  7. Artwohl M, Furnsinn C, Waldhausl W, Holzenbein T, Rainer G, Freudenthaler A, Roden M, Baumgartner-Parzer SM: Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPARgamma-independent mechanism. Diabetologia. 2005 Mar;48(3):586-94. Epub 2005 Feb 24. [15729575 ]
  8. Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW: Type 2 deiodinase expression is induced by peroxisomal proliferator-activated receptor-gamma agonists in skeletal myocytes. Endocrinology. 2009 Apr;150(4):1976-83. doi: 10.1210/en.2008-0938. Epub 2008 Nov 26. [19036883 ]
  9. Fakhrudin N, Ladurner A, Atanasov AG, Heiss EH, Baumgartner L, Markt P, Schuster D, Ellmerer EP, Wolber G, Rollinger JM, Stuppner H, Dirsch VM: Computer-aided discovery, validation, and mechanistic characterization of novel neolignan activators of peroxisome proliferator-activated receptor gamma. Mol Pharmacol. 2010 Apr;77(4):559-66. doi: 10.1124/mol.109.062141. Epub 2010 Jan 11. [20064974 ]
  10. Thieme TM, Steri R, Proschak E, Paulke A, Schneider G, Schubert-Zsilavecz M: Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2469-73. doi: 10.1016/j.bmcl.2010.03.008. Epub 2010 Mar 4. [20307981 ]
  11. Atanasov AG, Wang JN, Gu SP, Bu J, Kramer MP, Baumgartner L, Fakhrudin N, Ladurner A, Malainer C, Vuorinen A, Noha SM, Schwaiger S, Rollinger JM, Schuster D, Stuppner H, Dirsch VM, Heiss EH: Honokiol: a non-adipogenic PPARgamma agonist from nature. Biochim Biophys Acta. 2013 Oct;1830(10):4813-9. doi: 10.1016/j.bbagen.2013.06.021. Epub 2013 Jun 27. [23811337 ]
  12. Murakami K, Tobe K, Ide T, Mochizuki T, Ohashi M, Akanuma Y, Yazaki Y, Kadowaki T: A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes. 1998 Dec;47(12):1841-7. [9836514 ]
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
References
  1. Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S: Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochem Biophys Res Commun. 2002 Jan 11;290(1):131-9. [11779144 ]
  2. Sarath Josh MK, Pradeep S, Vijayalekshmi Amma KS, Balachandran S, Abdul Jaleel UC, Doble M, Spener F, Benjamin S: Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor alpha, beta, gamma subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11. [23843199 ]
General Function:
Zinc ion binding
Specific Function:
Ligand-activated transcription factor. Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Has a preference for poly-unsaturated fatty acids, such as gamma-linoleic acid and eicosapentanoic acid. Once activated by a ligand, the receptor binds to promoter elements of target genes. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the acyl-CoA oxidase gene. Decreases expression of NPC1L1 once activated by a ligand.
Gene Name:
PPARD
Uniprot ID:
Q03181
Molecular Weight:
49902.99 Da
References
  1. Sarath Josh MK, Pradeep S, Vijayalekshmi Amma KS, Balachandran S, Abdul Jaleel UC, Doble M, Spener F, Benjamin S: Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor alpha, beta, gamma subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11. [23843199 ]