Tmic
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Record Information
Version2.0
Creation Date2014-09-11 05:16:26 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4784
Identification
Common NameClofibrate
ClassSmall Molecule
DescriptionA fibric acid derivative used in the treatment of hyperlipoproteinemia type III and severe hypertriglyceridemia.
Compound Type
  • Anticholesteremic Agent
  • Drug
  • Ester
  • Ether
  • Hypolipidemic Agent
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
2-(4-Chlorophenoxy)-2-methylpropanoic acid ethyl ester
2-(p-Chlorophenoxy)-2-methylpropionic acid ethyl ester
alpha-(p-Chlorophenoxy)isobutyric acid, ethyl ester
alpha-p-Chlorophenoxyisobutyryl ethyl ester
Alufibrate
Atromid-S
Binograc
Chlorfenisate
Chlorphenisate
Clobrate
Clofibate
Clofibrato
Clofibratum
Clofibric acid
CPIB
ELPI
EPIB
Ethyl 2-(P-chlorophenoxy)isobutyrate
Ethyl chlorophenoxyisobutyrate
Ethyl clofibrate
Ethyl p-chlorophenoxyisobutyrate
Ethyl para-chlorophenoxyisobutyrate
Hisunsero
Koliva
Lipofacton
Liprin
Myanlin
Chemical FormulaC12H15ClO3
Average Molecular Mass242.699 g/mol
Monoisotopic Mass242.071 g/mol
CAS Registry Number637-07-0
IUPAC Nameethyl 2-(4-chlorophenoxy)-2-methylpropanoate
Traditional Nameartes
SMILESCCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1
InChI IdentifierInChI=1S/C12H15ClO3/c1-4-15-11(14)12(2,3)16-10-7-5-9(13)6-8-10/h5-8H,4H2,1-3H3
InChI KeyInChIKey=KNHUKKLJHYUCFP-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenoxyacetic acid derivatives. Phenoxyacetic acid derivatives are compounds containing an anisole where the methane group is linked to an acetic acid or a derivative.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenoxyacetic acid derivatives
Direct ParentPhenoxyacetic acid derivatives
Alternative Parents
Substituents
  • Phenoxyacetate
  • Phenoxy compound
  • Phenol ether
  • Alkyl aryl ether
  • Chlorobenzene
  • Halobenzene
  • Aryl chloride
  • Aryl halide
  • Carboxylic acid ester
  • Carboxylic acid derivative
  • Ether
  • Monocarboxylic acid or derivatives
  • Organochloride
  • Organooxygen compound
  • Organic oxygen compound
  • Carbonyl group
  • Hydrocarbon derivative
  • Organohalogen compound
  • Organic oxide
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic 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
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point118-119°C
Boiling Point149°C at 2.00E+01 mm Hg
SolubilityInsoluble
LogP3.3
Predicted Properties
PropertyValueSource
Water Solubility0.029 g/LALOGPS
logP3.99ALOGPS
logP3.4ChemAxon
logS-3.9ALOGPS
pKa (Strongest Basic)-4.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.53 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity62.14 m³·mol⁻¹ChemAxon
Polarizability24.7 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00or-4900000000-b0f27a4473b7e59d68c3View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-0390000000-a206c9f16b476083dcdbView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004i-1920000000-cdf7fd63fdcb1f2840cdView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-004i-6900000000-bf1eef6ec7349495a9b5View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0290000000-f8e44478c85e8deb28e7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004l-1960000000-5686cbdf03cff625cebcView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004i-2900000000-de1ce5552c1bea344c1eView in MoNA
MSMass Spectrum (Electron Ionization)splash10-004i-3900000000-fc2f01df51d424557e9fView in MoNA
Toxicity Profile
Route of ExposureCompletely but slowly absorbed from the intestine. Between 95% and 99% of an oral dose of clofibrate is excreted in the urine as free and conjugated clofibric acid; thus, the absorption of clofibrate is virtually complete.
Mechanism of ToxicityClofibrate increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis. Chylomicrons are degraded, VLDLs are converted to LDLs, and LDLs are converted to HDL. This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine. Clofibrate also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL. Also, as a fibrate, Clofibrate is an agonist of the PPAR-‘± receptor[4] in muscle, liver, and other tissues. This agonism ultimately leads to modification in gene expression resulting in increased beta-oxidation, decreased triglyceride secretion, increased HDL, increased lipoprotein lipase activity.
MetabolismHepatic and gastrointestinal: rapid de-esterification occurs in the gastrointestinal tract and/or on first-pass metabolism to produce the active form, clofibric acid (chlorophenoxy isobutyric acid [CPIB]). Half Life: Half-life in normal volunteers averages 18 to 22 hours (range 14 to 35 hours) but can vary by up to 7 hours in the same subject at different times.
Toxicity ValuesOral, mouse: LD50 = 1220 mg/kg; Oral, rabbit: LD50 = 1370 mg/kg; Oral, rat: LD50 = 940 mg/kg.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (1)
Uses/SourcesFor Primary Dysbetalipoproteinemia (Type III hyperlipidemia) that does not respond adequately to diet. This helps control high cholesterol and high triglyceride levels.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00636
HMDB IDHMDB14774
PubChem Compound ID2796
ChEMBL IDCHEMBL565
ChemSpider ID2694
KEGG IDC06916
UniProt IDNot Available
OMIM ID
ChEBI ID3750
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkClofibrate
References
Synthesis Reference

Jones, W.G.M.,Thorp, J.M. and Waring, W.S.; U.S. Patent 3,262,850; July 26, 1966; assigned to Imperial Chemical Industries Limited, England.

MSDSLink
General References
  1. 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:
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. Barclay TB, Peters JM, Sewer MB, Ferrari L, Gonzalez FJ, Morgan ET: Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent. J Pharmacol Exp Ther. 1999 Sep;290(3):1250-7. [10454501 ]
  2. Murata M, Kaji H, Takahashi Y, Iida K, Mizuno I, Okimura Y, Abe H, Chihara K: Stimulation by eicosapentaenoic acids of leptin mRNA expression and its secretion in mouse 3T3-L1 adipocytes in vitro. Biochem Biophys Res Commun. 2000 Apr 13;270(2):343-8. [10753628 ]
  3. Hunt MC, Lindquist PJ, Peters JM, Gonzalez FJ, Diczfalusy U, Alexson SE: Involvement of the peroxisome proliferator-activated receptor alpha in regulating long-chain acyl-CoA thioesterases. J Lipid Res. 2000 May;41(5):814-23. [10787442 ]
  4. Casas F, Domenjoud L, Rochard P, Hatier R, Rodier A, Daury L, Bianchi A, Kremarik-Bouillaud P, Becuwe P, Keller J, Schohn H, Wrutniak-Cabello C, Cabello G, Dauca M: A 45 kDa protein related to PPARgamma2, induced by peroxisome proliferators, is located in the mitochondrial matrix. FEBS Lett. 2000 Jul 28;478(1-2):4-8. [10922459 ]
  5. Komuves LG, Hanley K, Lefebvre AM, Man MQ, Ng DC, Bikle DD, Williams ML, Elias PM, Auwerx J, Feingold KR: Stimulation of PPARalpha promotes epidermal keratinocyte differentiation in vivo. J Invest Dermatol. 2000 Sep;115(3):353-60. [10951268 ]
  6. Gelosa P, Banfi C, Gianella A, Brioschi M, Pignieri A, Nobili E, Castiglioni L, Cimino M, Tremoli E, Sironi L: Peroxisome proliferator-activated receptor {alpha} agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats. J Pharmacol Exp Ther. 2010 Nov;335(2):324-31. doi: 10.1124/jpet.110.171090. Epub 2010 Jul 29. [20671072 ]
  7. Palkar PS, Anderson CR, Ferry CH, Gonzalez FJ, Peters JM: Effect of prenatal peroxisome proliferator-activated receptor alpha (PPARalpha) agonism on postnatal development. Toxicology. 2010 Sep 30;276(1):79-84. doi: 10.1016/j.tox.2010.07.008. Epub 2010 Jul 15. [20637823 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC500.0315 uMTox21_ERa_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 ]