Tmic
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Record Information
Version2.0
Creation Date2014-10-14 21:16:12 UTC
Update Date2014-12-24 20:27:01 UTC
Accession NumberT3D4976
Identification
Common NameClomifene
ClassSmall Molecule
DescriptionA triphenyl ethylene stilbene derivative which is an estrogen agonist or antagonist depending on the target tissue. [PubChem]
Compound Type
  • Drug
  • Estrogen Antagonist
  • Fertility Agent, Female
  • Metabolite
  • Selective Estrogen Receptor Modulator
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Androxal
Chlomaphene
Chloramifene
Chloramiphene
Cisclomiphene
Clomid
Clomifene citrate
Clomifeno
Clomifenum
Clomifert
Clomiphene
Clomiphene Citrate
Clomiphene citrate (Z,E)
Clostilbegyt
Omifin
Racemic clomiphene citrate
Serophene
Zuclomiphene citrate
Chemical FormulaC26H28ClNO
Average Molecular Mass405.960 g/mol
Monoisotopic Mass405.186 g/mol
CAS Registry Number911-45-5
IUPAC Name{2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]ethyl}diethylamine
Traditional Namepioner
SMILESCCN(CC)CCOC1=CC=C(C=C1)C(=C(\Cl)C1=CC=CC=C1)\C1=CC=CC=C1
InChI IdentifierInChI=1S/C26H28ClNO/c1-3-28(4-2)19-20-29-24-17-15-22(16-18-24)25(21-11-7-5-8-12-21)26(27)23-13-9-6-10-14-23/h5-18H,3-4,19-20H2,1-2H3/b26-25+
InChI KeyInChIKey=GKIRPKYJQBWNGO-OCEACIFDSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassStilbenes
Sub ClassNot Available
Direct ParentStilbenes
Alternative Parents
Substituents
  • Stilbene
  • Diphenylmethane
  • Phenoxy compound
  • Phenol ether
  • Alkyl aryl ether
  • Monocyclic benzene moiety
  • Benzenoid
  • Tertiary amine
  • Tertiary aliphatic amine
  • Ether
  • Chloroalkene
  • Haloalkene
  • Vinyl halide
  • Vinyl chloride
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Amine
  • Organic oxygen compound
  • Organopnictogen compound
  • 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
AppearanceNot Available
Experimental Properties
PropertyValue
Melting Point116.5-118 °C
Boiling PointNot Available
SolubilitySlightly soluble
LogP7.2
Predicted Properties
PropertyValueSource
Water Solubility0.00041 g/LALOGPS
logP6.08ALOGPS
logP6.47ChemAxon
logS-6ALOGPS
pKa (Strongest Basic)9.31ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity133.76 m³·mol⁻¹ChemAxon
Polarizability46.7 ųChemAxon
Number of Rings3ChemAxon
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, Positivesplash10-052r-9012000000-45df4fe468787edb6d89View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0a4i-0000900000-6e563271338e3449b9f0View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-0000900000-6e563271338e3449b9f0View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-1312900000-ca9aa2374db80c007b5fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udr-4933200000-164fa87cdbe23cc72977View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0fi9-9451000000-5927a010de880212b24fView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-1323900000-270e95f39bc9c23eae50View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0pb9-4129400000-86f55d0b88e5983df5a4View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-05i0-9454000000-848ee095f1842299cd00View in MoNA
Toxicity Profile
Route of ExposureBased on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.
Mechanism of ToxicityClomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.
MetabolismHepatic
Toxicity ValuesThe acute oral LD50 of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosage of clomifene have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (9)
Uses/SourcesUsed mainly in female infertility due to anovulation (e.g. due to polycystic ovary syndrome) to induce ovulation.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00882
HMDB IDHMDB15020
PubChem Compound ID1548953
ChEMBL IDCHEMBL1200667
ChemSpider ID1265967
KEGG IDC06917
UniProt IDNot Available
OMIM ID
ChEBI ID3752
BioCyc IDNot Available
CTD IDD002996
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkClomifene
References
Synthesis Reference

Allen, R.E., Palopoli, F.P., Schumann, E.L. and Van Carnpen, M.G. Jr.; US. Patent 2,914,563; November 24, 1959; assigned to The Wrn. S. Merrell Company.

MSDST3D4976.pdf
General References
  1. Purvin VA: Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol. 1995 Apr;113(4):482-4. [7710399 ]
  2. Hayon T, Atlas L, Levy E, Dvilansky A, Shpilberg O, Nathan I: Multifactorial activities of nonsteroidal antiestrogens against leukemia. Cancer Detect Prev. 2003;27(5):389-96. [14585326 ]
  3. Fritz MA, Holmes RT, Keenan EJ: Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women. Am J Obstet Gynecol. 1991 Jul;165(1):177-85. [1906682 ]
  4. Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. doi: 10.1002/14651858.CD000057.pub2. [20091498 ]
  5. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. doi: 10.1002/14651858.CD002249.pub4. [19821295 ]
  6. Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. [17055820 ]
  7. Homburg R: Oral agents for ovulation induction--clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. doi: 10.1080/14647270701689670. [18320435 ]
  8. Homburg R: Clomiphene citrate--end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. [15878925 ]
  9. 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 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
References
  1. Sasson S: Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol Biol (Paris). 1991 Jan;39(1):59-69. [2011412 ]
  2. Kurosawa T, Hiroi H, Momoeda M, Inoue S, Taketani Y: Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors alpha and beta. Endocr J. 2010;57(6):517-21. Epub 2010 Apr 6. [20379036 ]
  3. Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. doi: 10.1002/14651858.CD000057.pub2. [20091498 ]
  4. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. doi: 10.1002/14651858.CD002249.pub4. [19821295 ]
  5. Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. [17055820 ]
  6. Overbeek A, Lambalk N: Pharmacogenomics of ovulation induction: facilitating decisions on who, when and how to treat. Pharmacogenomics. 2009 Sep;10(9):1377-9. doi: 10.2217/pgs.09.110. [19761360 ]
  7. Homburg R: Oral agents for ovulation induction--clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. doi: 10.1080/14647270701689670. [18320435 ]
  8. Homburg R: Clomiphene citrate--end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. [15878925 ]
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  10. Fukuzawa K, Kitaura K, Uebayasi M, Nakata K, Kaminuma T, Nakano T: Ab initio quantum mechanical study of the binding energies of human estrogen receptor alpha with its ligands: an application of fragment molecular orbital method. J Comput Chem. 2005 Jan 15;26(1):1-10. [15521089 ]
  11. Bovet C, Plet B, Ruff M, Eiler S, Granger F, Panagiotidis A, Wenzel R, Nazabal A, Moras D, Zenobi R: Towards high-throughput identification of endocrine disrupting compounds with mass spectrometry. Toxicol In Vitro. 2009 Jun;23(4):704-9. doi: 10.1016/j.tiv.2009.02.004. Epub 2009 Feb 20. [19233257 ]
General Function:
Zinc ion binding
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 (PubMed:20074560). 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:
59215.765 Da
References
  1. Han DH, Denison MS, Tachibana H, Yamada K: Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci Biotechnol Biochem. 2002 Jul;66(7):1479-87. [12224631 ]