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Record Information
Version4.0
StatusExpected but not Quantified
Creation Date2012-09-06 15:16:49 UTC
Update Date2020-02-26 21:40:00 UTC
HMDB IDHMDB0014624
Secondary Accession Numbers
  • HMDB14624
Metabolite Identification
Common NameRaloxifene
DescriptionRaloxifene is only found in individuals that have used or taken this drug. It is a second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [PubChem]. Raloxifene binds to estrogen receptors, resulting in differential expression of multiple estrogen-regulated genes in different tissues. Raloxifene produces estrogen-like effects on bone, reducing resorption of bone and increasing bone mineral density in postmenopausal women, thus slowing the rate of bone loss. The maintenance of bone mass by raloxifene and estrogens is, in part, through the regulation of the gene-encoding transforming growth factor-β3 (TGF-β3), which is a bone matrix protein with antiosteoclastic properties. Raloxifene activates TGF-β3 through pathways that are estrogen receptor-mediated but involve DNA sequences distinct from the estrogen response element. The drug also binds to the estrogen receptor and acts as an estrogen agonist in preosteoclastic cells, which results in the inhibtion of their proliferative capacity. This inhibition is thought to contribute to the drug's effect on bone resorption. Other mechanisms include the suppression of activity of the bone-resorbing cytokine interleukin-6 promoter activity. Raloxifene also antagonizes the effects of estrogen on mammary tissue and blocks uterotrophic responses to estrogen. By competing with estrogens for the estrogen receptors in reproductive tissue, raloxifene prevents the transcriptional activation of genes containing the estrogen response element. As well, raloxifene inhibits the estradiol-dependent proliferation of MCF-7 human mammary tumor cells in vitro. The mechansim of action of raloxifene has not been fully determined, but evidence suggests that the drug's tissue-specific estrogen agonist or antagonist activity is related to the structural differences between the raloxifene-estrogen receptor complex (specifically the surface topography of AF-2) and the estrogen-estrogen receptor complex. Also, the existence of at least 2 estrogen receptors (ERα, ERβ) may contribute to the tissue specificity of raloxifene.
Structure
Data?1582753200
Synonyms
ValueSource
(2-(4-Hydroxyphenyl)-6-hydroxybenzo(b)thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)methanoneChEBI
KeoxifeneChEBI
LY 139481ChEBI
RaloxifenoChEBI
RaloxifenumChEBI
EvidenKegg
RaxetoKegg
LY-139481HMDB
RALHMDB
Raloxifene hydrochlorideHMDB
EvistaHMDB
Keoxifene hydrochlorideHMDB
Raloxifene HCLHMDB
Chemical FormulaC28H27NO4S
Average Molecular Weight473.583
Monoisotopic Molecular Weight473.166079047
IUPAC Name2-(4-hydroxyphenyl)-3-{4-[2-(piperidin-1-yl)ethoxy]benzoyl}-1-benzothiophen-6-ol
Traditional Nameraloxifene
CAS Registry Number84449-90-1
SMILES
OC1=CC=C(C=C1)C1=C(C(=O)C2=CC=C(OCCN3CCCCC3)C=C2)C2=C(S1)C=C(O)C=C2
InChI Identifier
InChI=1S/C28H27NO4S/c30-21-8-4-20(5-9-21)28-26(24-13-10-22(31)18-25(24)34-28)27(32)19-6-11-23(12-7-19)33-17-16-29-14-2-1-3-15-29/h4-13,18,30-31H,1-3,14-17H2
InChI KeyGZUITABIAKMVPG-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as aryl-phenylketones. These are aromatic compounds containing a ketone substituted by one aryl group, and a phenyl group.
KingdomOrganic compounds
Super ClassOrganic oxygen compounds
ClassOrganooxygen compounds
Sub ClassCarbonyl compounds
Direct ParentAryl-phenylketones
Alternative Parents
Substituents
  • Aryl-phenylketone
  • 3-aroylthiophene
  • Benzothiophene
  • 1-benzothiophene
  • Phenoxy compound
  • Benzoyl
  • Phenol ether
  • Thiophene carboxylic acid or derivatives
  • Alkyl aryl ether
  • 1-hydroxy-2-unsubstituted benzenoid
  • Phenol
  • Monocyclic benzene moiety
  • Benzenoid
  • Piperidine
  • Heteroaromatic compound
  • Thiophene
  • Tertiary aliphatic amine
  • Tertiary amine
  • Organoheterocyclic compound
  • Azacycle
  • Ether
  • Organonitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic nitrogen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Ontology
Disposition

Biological location:

Role

Industrial application:

Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting Point143 - 147 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.00051 g/LNot Available
LogP5.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00051 g/LALOGPS
logP5.45ALOGPS
logP5.69ChemAxon
logS-6ALOGPS
pKa (Strongest Acidic)8.89ChemAxon
pKa (Strongest Basic)7.95ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area70 ŲChemAxon
Rotatable Bond Count7ChemAxon
Refractivity135.48 m³·mol⁻¹ChemAxon
Polarizability52.55 ųChemAxon
Number of Rings5ChemAxon
BioavailabilityYesChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-006t-9112200000-194dfc7c577ba3e76b98Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-0udj-9010136000-3bb502413414534da20bSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0229-0035900000-dcf0b4afb1abd2691c7cSpectrum
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0229-6600900000-ea14790ae9aed263379bSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0114900000-e8c217b2f20574044c33Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03xs-4984400000-a2731ab247793dc0402eSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014u-7296000000-82a010336a5451ab7f97Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00di-1012900000-c3bc16da6ed53c190cf7Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-03kc-2149500000-8a3b4929414c1ff5dc90Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00l6-5596000000-26179eaf5995f4a2067bSpectrum
Biological Properties
Cellular Locations
  • Cytoplasm
  • Membrane
Biospecimen Locations
  • Blood
  • Urine
Tissue LocationsNot Available
Pathways
Normal Concentrations
BiospecimenStatusValueAgeSexConditionReferenceDetails
BloodExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00481 details
UrineExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00481 details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB00481
Phenol Explorer Compound IDNot Available
FooDB IDNot Available
KNApSAcK IDNot Available
Chemspider ID4859
KEGG Compound IDC07228
BioCyc IDNot Available
BiGG IDNot Available
Wikipedia LinkRaloxifene
METLIN IDNot Available
PubChem Compound5035
PDB IDNot Available
ChEBI ID8772
Food Biomarker OntologyNot Available
VMH IDNot Available
MarkerDB ID
References
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Balfour JA, Goa KL: Raloxifene. Drugs Aging. 1998 Apr;12(4):335-41; discussion 342. [PubMed:9571395 ]
  2. Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999 Mar 2;130(5):431-9. [PubMed:10068418 ]
  3. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999 Jun 16;281(23):2189-97. [PubMed:10376571 ]
  4. Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44. [PubMed:10418979 ]
  5. Clemett D, Spencer CM: Raloxifene: a review of its use in postmenopausal osteoporosis. Drugs. 2000 Aug;60(2):379-411. [PubMed:10983739 ]
  6. Barrett-Connor E: Raloxifene: risks and benefits. Ann N Y Acad Sci. 2001 Dec;949:295-303. [PubMed:11795366 ]
  7. Heringa M: Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther. 2003 Aug;41(8):331-45. [PubMed:12940590 ]
  8. Authors unspecified: A STARring role for raloxifene? Lancet Oncol. 2006 Jun;7(6):443. [PubMed:16750489 ]
  9. Diez-Perez A: Selective estrogen receptor modulators (SERMS). Arq Bras Endocrinol Metabol. 2006 Aug;50(4):720-34. [PubMed:17117297 ]
  10. Silverman SL: New selective estrogen receptor modulators (SERMs) in development. Curr Osteoporos Rep. 2010 Sep;8(3):151-3. doi: 10.1007/s11914-010-0025-0. [PubMed:20603714 ]

Enzymes

General function:
Involved in oxidoreductase activity
Specific function:
Not Available
Gene Name:
AOX1
Uniprot ID:
Q06278
Molecular weight:
147916.735
References
  1. Obach RS: Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab Dispos. 2004 Jan;32(1):89-97. [PubMed:14709625 ]
  2. Obach RS, Huynh P, Allen MC, Beedham C: Human liver aldehyde oxidase: inhibition by 239 drugs. J Clin Pharmacol. 2004 Jan;44(1):7-19. [PubMed:14681337 ]
  3. Sahi J, Khan KK, Black CB: Aldehyde oxidase activity and inhibition in hepatocytes and cytosolic fractions from mouse, rat, monkey and human. Drug Metab Lett. 2008 Aug;2(3):176-83. [PubMed:19356090 ]
General function:
Involved in sequence-specific DNA binding transcription factor activity
Specific function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner. Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA- binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual
Gene Name:
ESR2
Uniprot ID:
Q92731
Molecular weight:
59215.8
References
  1. Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44. [PubMed:10418979 ]
  2. Iannone MA, Consler TG, Pearce KH, Stimmel JB, Parks DJ, Gray JG: Multiplexed molecular interactions of nuclear receptors using fluorescent microspheres. Cytometry. 2001 Aug 1;44(4):326-37. [PubMed:11500849 ]
  3. Zhou W, Koldzic-Zivanovic N, Clarke CH, de Beun R, Wassermann K, Bury PS, Cunningham KA, Thomas ML: Selective estrogen receptor modulator effects in the rat brain. Neuroendocrinology. 2002 Jan;75(1):24-33. [PubMed:11810032 ]
  4. Sun J, Huang YR, Harrington WR, Sheng S, Katzenellenbogen JA, Katzenellenbogen BS: Antagonists selective for estrogen receptor alpha. Endocrinology. 2002 Mar;143(3):941-7. [PubMed:11861516 ]
  5. Kim IY, Seong DH, Kim BC, Lee DK, Remaley AT, Leach F, Morton RA, Kim SJ: Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. Cancer Res. 2002 Jul 1;62(13):3649-53. [PubMed:12097269 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
General function:
Involved in monooxygenase activity
Specific function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular weight:
57255.585
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
General function:
Involved in monooxygenase activity
Specific function:
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. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular weight:
56277.81
References
  1. Walsky RL, Astuccio AV, Obach RS: Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol. 2006 Dec;46(12):1426-38. [PubMed:17101742 ]
General function:
Involved in monooxygenase activity
Specific function:
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name:
CYP19A1
Uniprot ID:
P11511
Molecular weight:
57882.48
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
General function:
Involved in monooxygenase activity
Specific function:
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).
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular weight:
55824.275
References
  1. Walsky RL, Gaman EA, Obach RS: Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78. [PubMed:15601807 ]
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
General function:
Involved in sequence-specific DNA binding transcription factor activity
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. Can activate the transcriptional activity of TFF1
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular weight:
66215.4
References
  1. Khovidhunkit W, Shoback DM: Clinical effects of raloxifene hydrochloride in women. Ann Intern Med. 1999 Mar 2;130(5):431-9. [PubMed:10068418 ]
  2. Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999 Jun 16;281(23):2189-97. [PubMed:10376571 ]
  3. Bryant HU, Glasebrook AL, Yang NN, Sato M: An estrogen receptor basis for raloxifene action in bone. J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):37-44. [PubMed:10418979 ]
  4. Figtree GA, Lu Y, Webb CM, Collins P: Raloxifene acutely relaxes rabbit coronary arteries in vitro by an estrogen receptor-dependent and nitric oxide-dependent mechanism. Circulation. 1999 Sep 7;100(10):1095-101. [PubMed:10477535 ]
  5. Schafer JI, Liu H, Tonetti DA, Jordan VC: The interaction of raloxifene and the active metabolite of the antiestrogen EM-800 (SC 5705) with the human estrogen receptor. Cancer Res. 1999 Sep 1;59(17):4308-13. [PubMed:10485477 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  7. Scott JA, Da Camara CC, Early JE: Raloxifene: a selective estrogen receptor modulator. Am Fam Physician. 1999 Sep 15;60(4):1131-9. [PubMed:10507743 ]
  8. Matsumoto T: [Selective estrogen receptor modulators (SERMs)]. Clin Calcium. 2006 Sep;16(9):1520-25. [PubMed:16951478 ]
  9. Moen MD, Keating GM: Raloxifene: a review of its use in the prevention of invasive breast cancer. Drugs. 2008;68(14):2059-83. [PubMed:18778124 ]