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Record Information
Version2.0
Creation Date2014-09-11 05:17:18 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4803
Identification
Common NameLetrozole
ClassSmall Molecule
DescriptionLetrozole (INN, trade name Femara®) is an oral non-steroidal aromatase inhibitor that has been introduced for the adjuvant treatment of hormonally-responsive breast cancer. Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Letrozole blocks production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids. In contrast, the antiestrogenic action of tamoxifen, the major medical therapy prior to the arrival of aromatase inhibitors, is due to its interfering with the estrogen receptor, rather than inhibiting estrogen production. Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women. Side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is why prescriptions of Letrozole are often accompanied by prescriptions of osteoporosis-fighting medication such as Fosamax. Letrozole has shown to reduce estrogen levels by 98 percent while raising testosterone levels. The anti-estrogen action of letrozole is preferred by athletes and bodybuilders for use during a steroid cycle to reduce bloating due to excess water retention and prevent the formation of gynecomastia related breast tissue that is a side effect of some anabolic steroids. Usage above 2.5 mg/day is known to potentially temporarily kill sex drive. Above 5mg/day for extended periods may cause kidney problems. Letrozole has also been shown to delay the fusing of the growth plates in adolescents. This may boost the effectiveness of growth hormone, and thus Letrozole is used to treat adolescents and children with short stature.
Compound Type
  • Amine
  • Antineoplastic Agent
  • Aromatase Inhibitor
  • Drug
  • Metabolite
  • Nitrile
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
Femara
Letrozol
Chemical FormulaC17H11N5
Average Molecular Mass285.303 g/mol
Monoisotopic Mass285.101 g/mol
CAS Registry Number112809-51-5
IUPAC Name4-[(4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl]benzonitrile
Traditional Nameletrozole
SMILESN#CC1=CC=C(C=C1)C(N1C=NC=N1)C1=CC=C(C=C1)C#N
InChI IdentifierInChI=1S/C17H11N5/c18-9-13-1-5-15(6-2-13)17(22-12-20-11-21-22)16-7-3-14(10-19)4-8-16/h1-8,11-12,17H
InChI KeyInChIKey=HPJKCIUCZWXJDR-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as diphenylmethanes. Diphenylmethanes are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassDiphenylmethanes
Direct ParentDiphenylmethanes
Alternative Parents
Substituents
  • Diphenylmethane
  • Benzonitrile
  • Heteroaromatic compound
  • 1,2,4-triazole
  • Azole
  • Azacycle
  • Organoheterocyclic compound
  • Nitrile
  • Carbonitrile
  • Organic nitrogen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic 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 Point184-185°C
Boiling PointNot Available
Solubility7.99e-02 g/L
LogP2.5
Predicted Properties
PropertyValueSource
Water Solubility0.08 g/LALOGPS
logP1.86ALOGPS
logP2.94ChemAxon
logS-3.6ALOGPS
pKa (Strongest Basic)2.17ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area78.29 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity94.47 m³·mol⁻¹ChemAxon
Polarizability29.59 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, Positivesplash10-014i-5390000000-96e7cbf457562ce8f33aJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-001i-0090000000-0fbd577a32ff572f7368JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-001i-0190000000-dfcab9af789387521571JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-0006-0390000000-dbc68fd6017abe6e8adcJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00kf-0490000000-c3fc389848a06a012234JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-014l-0690000000-38ba597054b02b136ab6JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00kf-1980000000-13a8827cbc5c1b36a14fJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00kf-3940000000-e01d63313ef1cfa7477aJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-014i-9410000000-83b93aed0756bd41adafJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-014i-9100000000-d1757f8c218d5dcc4809JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-014i-0090000000-791121bd513899b7dfc0JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-014i-0090000000-eb3996846ea4f036cccaJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-014i-0390000000-a57ce4cfb24ba743c54bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0006-0950000000-303d99867511fe3a013bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0006-0930000000-77e720374927be5113efJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0006-0920000000-4a93d8e76eb7d0d59481JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03du-0910000000-8ad9f37884e8686ef7baJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03dr-2900000000-2274a3adb5e486f57001JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-03dr-6900000000-74d56231c43250bc65caJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-014i-0490000000-7868daa9f0ec9ebda34aJSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-000i-0090000000-da3910c6e2a706e174c5JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001r-0090000000-f03b188334168da247e1JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-003r-1970000000-d83cde690a839474f8d6JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-001i-0090000000-f0fe35676feb362f0824JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-001i-0090000000-b517dd9b4d5a4a7b26a2JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-053r-2290000000-f5f7a0dda898f84a52afJSpectraViewer
Toxicity Profile
Route of ExposureRapidly and completely absorbed. Absorption is not affected by food.
Mechanism of ToxicityLetrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumorbearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Leuteinizing hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum (folicile stimulating hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis. Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (2)
MetabolismPrimarily hepatic via CYP3A4 and CYP2A6. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. Half Life: 2 days
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. Also for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01006
HMDB IDHMDB15141
PubChem Compound ID3902
ChEMBL IDCHEMBL1444
ChemSpider ID3765
KEGG IDC08163
UniProt IDNot Available
OMIM ID
ChEBI ID6413
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkLetrozole
References
Synthesis Reference

Peter MacDonald, Ettore Bigatti, Pierluigi Rossetto, Zvi Harel, “Process for the preparation of letrozole.” U.S. Patent US20070066831, issued March 22, 2007.

MSDST3D4803.pdf
General References
  1. Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, Librach C, Greenblatt E, Casper RF: Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006 Jun;85(6):1761-5. Epub 2006 May 2. [16650422 ]
  2. Wikipedia. Cyanide poisoning. Last Updated 30 March 2009. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Oxygen binding
Specific Function:
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name:
CYP19A1
Uniprot ID:
P11511
Molecular Weight:
57882.48 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.58 uMNVS_ADME_hCYP19A1Novascreen
AC500.0113 uMTox21_Aromatase_InhibitionTox21/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:
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:
AR
Uniprot ID:
P10275
Molecular Weight:
98987.9 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.55 uMNVS_NR_hARNovascreen
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 ]