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Identification
NameLetrozole
Accession NumberDB01006  (APRD01066)
Typesmall molecule
Groupsapproved, investigational
Description

Letrozole (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.

Structure
Thumb
Synonyms
SynonymLanguageCode
FemaraNot AvailableNot Available
LetrozolNot AvailableNot Available
LetrozoleNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
FemaraNot Available
Brand mixturesNot Available
Categories
CAS number112809-51-5
WeightAverage: 285.3027
Monoisotopic: 285.101445377
Chemical FormulaC17H11N5
InChI KeyHPJKCIUCZWXJDR-UHFFFAOYSA-N
InChI
InChI=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
IUPAC Name
4-[(4-cyanophenyl)(1H-1,2,4-triazol-1-yl)methyl]benzonitrile
SMILES
N#CC1=CC=C(C=C1)C(N1C=NC=N1)C1=CC=C(C=C1)C#N
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassDiphenylmethanes
Direct parentDiphenylmethanes
Alternative parentsBenzonitriles; Triazoles; Nitriles; Polyamines
Substituentsbenzonitrile; 1,2,4-triazole; azole; polyamine; carbonitrile; nitrile; amine; organonitrogen compound
Classification descriptionThis compound belongs to the diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Pharmacology
IndicationFor 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.
PharmacodynamicsLetrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.
Mechanism of actionLetrozole 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.
AbsorptionRapidly and completely absorbed. Absorption is not affected by food.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Primarily 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.

SubstrateEnzymesProduct
Letrozole
4,4'-methanol-bisbenzonitrileDetails
Route of eliminationNot Available
Half life2 days
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9965
Blood Brain Barrier + 0.9737
Caco-2 permeable + 0.6347
P-glycoprotein substrate Non-substrate 0.8391
P-glycoprotein inhibitor I Non-inhibitor 0.8087
P-glycoprotein inhibitor II Non-inhibitor 0.9147
Renal organic cation transporter Non-inhibitor 0.5908
CYP450 2C9 substrate Non-substrate 0.7898
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.6843
CYP450 1A2 substrate Non-inhibitor 0.8374
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Non-inhibitor 0.923
CYP450 2C19 substrate Inhibitor 0.8993
CYP450 3A4 substrate Inhibitor 0.6451
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7027
Ames test Non AMES toxic 0.6371
Carcinogenicity Non-carcinogens 0.8926
Biodegradation Not ready biodegradable 0.9864
Rat acute toxicity 1.9916 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9261
hERG inhibition (predictor II) Non-inhibitor 0.8817
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
  • Mylan pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Femara 2.5 mg tablet16.87USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States49786721994-06-032011-06-03
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point184-185 °CNot Available
logP2.5Not Available
Predicted Properties
PropertyValueSource
water solubility7.99e-02 g/lALOGPS
logP1.86ALOGPS
logP2.94ChemAxon
logS-3.5ALOGPS
pKa (strongest basic)2.17ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count0ChemAxon
polar surface area78.29ChemAxon
rotatable bond count3ChemAxon
refractivity94.47ChemAxon
polarizability29.59ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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.

US20070066831
General Reference
  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. Pubmed
External Links
ResourceLink
KEGG DrugD00964
KEGG CompoundC08163
PubChem Compound3902
PubChem Substance46504610
ChemSpider3765
BindingDB13061
ChEBI6413
ChEMBLCHEMBL1444
Therapeutic Targets DatabaseDAP000626
PharmGKBPA450196
Drug Product Database2231384
RxListhttp://www.rxlist.com/cgi/generic2/letroz.htm
Drugs.comhttp://www.drugs.com/cdi/letrozole.html
WikipediaLetrozole
ATC CodesL02BG04
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelshow(112 KB)
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Cytochrome P450 19A1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Cytochrome P450 19A1 P11511 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Ebert AD, Bartley J, David M, Schweppe KW: [Aromatase inhibitors—theoretical concept and present experiences in the treatment of endometriosis] Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51. Pubmed
  3. Long BJ, Jelovac D, Handratta V, Thiantanawat A, MacPherson N, Ragaz J, Goloubeva OG, Brodie AM: Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model. J Natl Cancer Inst. 2004 Mar 17;96(6):456-65. Pubmed
  4. Murphy MJ Jr: Molecular Action and Clinical Relevance of Aromatase Inhibitors. Oncologist. 1998;3(2):129-130. Pubmed

Enzymes

1. Cytochrome P450 19A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 19A1 P11511 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2A6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2A6 P11509 Details

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. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12