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targets (1) enzymes (3)
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Identification
Name Letrozole
Accession Number DB01006 (APRD01066)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Letrozol
Salts Not Available
Brand names
Name Company
Femara
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Aromatase Inhibitors
CAS number 112809-51-5
Weight Average: 285.3027
Monoisotopic: 285.101445377
Chemical Formula C17H11N5
InChI Key InChIKey=HPJKCIUCZWXJDR-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Triazoles
  • Nitriles and Derivatives
  • Benzene and Derivatives
  • Cyanides
  • Diphenylmethanes
  • Heterocyclic compounds
  • Aromatic compounds
  • Cyanamides
Pharmacology
Indication For 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.
Pharmacodynamics Letrozole 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 action Letrozole 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.
Absorption Rapidly and completely absorbed. Absorption is not affected by food.
Volume of distribution Not Available
Protein binding Not 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.
Route of elimination Not Available
Half life 2 days
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
  • Mylan pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Femara 2.5 mg tablet 16.87 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 4978672 1994-06-03 2011-06-03
Properties
State solid
Experimental Properties
Property Value Source
melting point 184-185 °C Not Available
logP 2.5 Not Available
Predicted Properties
Property Value Source
water solubility 7.99e-02 g/l ALOGPS
logP 1.86 ALOGPS
logP 2.94 ChemAxon
logS -3.5 ALOGPS
pKa (strongest basic) 2.17 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 78.29 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 94.47 ChemAxon
polarizability 29.59 ChemAxon
References
Synthesis Reference Not Available
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
Resource Link
KEGG Drug D00964 Link_out
KEGG Compound C08163 Link_out
PubChem Compound 3902 Link_out
PubChem Substance 46504610 Link_out
ChemSpider 3765 Link_out
BindingDB 13061 Link_out
ChEBI 6413 Link_out
ChEMBL 6413 Link_out
Therapeutic Targets Database DAP000626 Link_out
PharmGKB PA450196 Link_out
Drug Product Database 2231384 Link_out
RxList http://www.rxlist.com/cgi/generic2/letroz.htm Link_out
Drugs.com http://www.drugs.com/cdi/letrozole.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Letrozole Link_out
ATC Codes
  • L02BG04
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label show (112 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals. Food slows absorption without decreasing the quantity absorbed.
Targets

1. Cytochrome P450 19A1

Pharmacological action: yes
Actions: antagonist

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

Organism class: human
UniProt ID: P11511 Link_out
Gene: CYP19A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

UniProt ID: P11511 Link_out
Gene: CYP19A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

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. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Constitutes the major nicotine C-oxidase

UniProt ID: P11509 Link_out
Gene: CYP2A6
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19