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Identification
Name Toremifene
Accession Number DB00539 (APRD00391)
Type small molecule
Groups approved
Description

A first generation nonsteroidal selective estrogen receptor modulator (SERM) that is structurally related to tamoxifen. Like tamoxifen, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • toremifene
Brand names
  • Acapodene
  • Fareston
  • Farestone
  • Toremifene Base
  • Toremifeno [Spanish]
  • Toremifenum [Latin]
  • Z-Toremifene
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antineoplastic Agents, Hormonal
  • Selective Estrogen Receptor Modulators
  • Bone Density Conservation Agents
CAS number 89778-26-7
Weight Average: 405.96
Monoisotopic: 405.185942230
Chemical Formula C26H28ClNO
InChI Key InChIKey=XFCLJVABOIYOMF-QPLCGJKRSA-N
InChI
InChI=1S/C26H28ClNO/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16H,17-20H2,1-2H3/b26-25-
Plain Text
IUPAC Name
(2-{4-[(1Z)-4-chloro-1,2-diphenylbut-1-en-1-yl]phenoxy}ethyl)dimethylamine
SMILES
CN(C)CCOC1=CC=C(C=C1)C(\C1=CC=CC=C1)=C(\CCCl)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Stilbenes
Substructures
  • Stilbenes
  • Alkanes and Alkenes
  • Phenols and Derivatives
  • Phenylpropenes
  • Ethers
  • Benzene and Derivatives
  • Aliphatic and Aryl Amines
  • Isoprenes
  • Alkyl Halides
  • Aromatic compounds
  • Anisoles
  • Styrene Derivatives
  • Phenyl Esters
Pharmacology
Indication For the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or receptor-unknown tumors. Toremifene is currently under investigation as a preventative agent for prostate cancer in men with high-grade prostatic intraepithelial neoplasia and no evidence of prostate cancer.
Pharmacodynamics Toremifene is an antineoplastic hormonal agent primarily used in the treatment of advanced breast cancer. Toremifene is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Toremifene inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, Toremifene appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, Toremifene competes with estradiol for estrogen receptor protein.
Mechanism of action Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, in other words, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene may also inhibit tumor growth through other mechanisms, such as induction of apoptosis, regulation of oncogene expression, and growth factors.
Absorption Well absorbed
Volume of distribution
  • 580 L
Protein binding Toremifen is primarily bound to albumin (92%), 2% bound to α1-acid glycoprotein, and 6% bound to β1-globulin in the serum.
Metabolism

Hepatic. Mainly by CYP3A4 to N-demethyltoremifene, which exhibits antiestrogenic effects but has weak antitumor potency in vivo.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 N-desmethyltoremifene N-demethylation 124 0.071
Route of elimination Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency.
Half life 5 days
Clearance
  • 5 L/h
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Gtx inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Fareston 60 mg tablet 11.84 USD tablet
Patents
Country Patent Number Approved Expires
United States 4696949 1992-09-29 2009-09-29
Properties
State solid
Melting point 108-110 oC
Experimental Properties
Property Value Source
logP 6.8 PhysProp
Predicted Properties
Property Value Source
water solubility 4.09e-04 g/l ALOGPS
logP 5.65 ALOGPS
logP 6.27 ChemAxon Molconvert
logS -6.00 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 2 ChemAxon Molconvert
hydrogen donor count 0 ChemAxon Molconvert
polar surface area 12.47 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 133.41 ChemAxon Molconvert
polarizability 46.49 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Price N, Sartor O, Hutson T, Mariani S: Role of 5a-reductase inhibitors and selective estrogen receptor modulators as potential chemopreventive agents for prostate cancer. Clin Prostate Cancer. 2005 Mar;3(4):211-4. Pubmed
  2. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA: Toremifene—a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy. Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. Pubmed
  3. Thompson IM: Chemoprevention of prostate cancer: agents and study designs. J Urol. 2007 Sep;178(3 Pt 2):S9-S13. Epub 2007 Jul 20. Pubmed
  4. Ariazi EA, Ariazi JL, Cordera F, Jordan VC: Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6(3):181-202. Pubmed
  5. Musa MA, Khan MO, Cooperwood JS: Medicinal chemistry and emerging strategies applied to the development of selective estrogen receptor modulators (SERMs). Curr Med Chem. 2007;14(11):1249-61. Pubmed
External Links
Resource Link
KEGG Compound C08166 Link_out
PubChem Compound 3005573 Link_out
PubChem Substance 46506087 Link_out
ChemSpider 2275722 Link_out
ChEBI 9635 Link_out
ChEMBL 9635 Link_out
Therapeutic Targets Database DAP000793 Link_out
PharmGKB PA451731 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic2/toremifene.htm Link_out
Drugs.com http://www.drugs.com/cdi/toremifene.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Toremifene Link_out
ATC Codes
  • L02BA02
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Estrogen receptor

Pharmacological action: yes
Actions: modulator

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

Organism class: human
UniProt ID: P03372 Link_out
Gene: ESR1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Locci P, Bellocchio S, Lilli C, Marinucci L, Cagini L, Baroni T, Giustozzi G, Balducci C, Becchetti E: Synthesis and secretion of transforming growth factor-beta1 by human desmoid fibroblast cell line and its modulation by toremifene. J Interferon Cytokine Res. 2001 Nov;21(11):961-70. Pubmed
  2. Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, Burdette JE, Bolton JL: Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Chem Res Toxicol. 2003 Jul;16(7):832-7. Pubmed
  3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  4. Jones KL, Buzdar AU: A review of adjuvant hormonal therapy in breast cancer. Endocr Relat Cancer. 2004 Sep;11(3):391-406. Pubmed
  5. Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB: Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv. 2008 Mar;63(3):163-81. Pubmed
  6. Gennari L, Merlotti D, Valleggi F, Martini G, Nuti R: Selective estrogen receptor modulators for postmenopausal osteoporosis: current state of development. Drugs Aging. 2007;24(5):361-79. Pubmed
  7. Lewis-Wambi JS, Jordan VC: Treatment of Postmenopausal Breast Cancer with Selective Estrogen Receptor Modulators (SERMs). Breast Dis. 2005-2006;24:93-105. Pubmed
  8. Ariazi EA, Ariazi JL, Cordera F, Jordan VC: Estrogen receptors as therapeutic targets in breast cancer. Curr Top Med Chem. 2006;6(3):181-202. Pubmed
  9. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA: Toremifene—a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy. Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. Pubmed
  10. Goldstein LJ: Controversies in adjuvant endocrine treatment of premenopausal women. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S36-40. Pubmed
  11. Smith MR: Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 2):6315s-6319s. Pubmed
Enzymes

1. 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. Taneja SS, Smith MR, Dalton JT, Raghow S, Barnette G, Steiner M, Veverka KA: Toremifene—a promising therapy for the prevention of prostate cancer and complications of androgen deprivation therapy. Expert Opin Investig Drugs. 2006 Mar;15(3):293-305. Pubmed
  2. Kivisto KT, Villikka K, Nyman L, Anttila M, Neuvonen PJ: Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin. Clin Pharmacol Ther. 1998 Dec;64(6):648-54. Pubmed
  3. 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 1A1

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P04798 Link_out
Gene: CYP1A1 Link_out
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 1A2

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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
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
Transporters

1. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Rao US, Fine RL, Scarborough GA: Antiestrogens and steroid hormones: substrates of the human P-glycoprotein. Biochem Pharmacol. 1994 Jul 19;48(2):287-92. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:04

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.