Identification

Name
Chlorotrianisene
Accession Number
DB00269  (APRD00715)
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

A powerful synthetic, non-steroidal estrogen. [PubChem]

Structure
Thumb
Synonyms
  • Chloortrianisestrol
  • Chlorestrolo
  • Chlorotrianisenum
  • Chlorotrianisine
  • Chlorotrianizen
  • Chlortrianisen
  • Chlortrianisestrol
  • Chlortrianisoestrolum
  • Chlortrianizen
  • Clorotrianiseno
External IDs
NSC-10108
International/Other Brands
Merbentul (Merrell) / Tace (Merrell) / Tace FN (Merrell) / Triagen (Gentili)
Categories
UNII
6V5034L121
CAS number
569-57-3
Weight
Average: 380.864
Monoisotopic: 380.117922245
Chemical Formula
C23H21ClO3
InChI Key
BFPSDSIWYFKGBC-UHFFFAOYSA-N
InChI
InChI=1S/C23H21ClO3/c1-25-19-10-4-16(5-11-19)22(17-6-12-20(26-2)13-7-17)23(24)18-8-14-21(27-3)15-9-18/h4-15H,1-3H3
IUPAC Name
1-[1-chloro-2,2-bis(4-methoxyphenyl)ethenyl]-4-methoxybenzene
SMILES
COC1=CC=C(C=C1)C(Cl)=C(C1=CC=C(OC)C=C1)C1=CC=C(OC)C=C1

Pharmacology

Indication

Used to treat symptoms of menopause, deficiencies in ovary function (including underdevelopment of female sexual characteristics and some types of infertility), and in rare cases, prostate cancer. Chlorotrianisene may also be used to prevent breast engorgement following childbirth.

Pharmacodynamics

Chlorotrianisene is a nonsteroidal synthetic estrogen. After menopause, when the body no longer produces estrogen, chlorotrianisene is used as a simple replacement of estrogen. The estrogen-stimulated endometrium may bleed within 48-72 hours after discontinuance of estrogen therapy. Paradoxically, prolonged estrogen therapy may cause shrinkage of the endometrium and an increase in size of the myometrium. Estrogens have a weak anabolic effect and may cause sodium retention with associated fluid retention and edema. Estrogens may also decrease elevated blood cholesterol and phospholipid concentrations. Estrogens affect bone by increasing calcium deposition and accelerating epiphyseal closure, following initial growth stimulation. During the preovulatory or nonovulatory phase of the menstrual cycle, estrogen is the principal determinant in the onset of menstruation. A decline of estrogenic activity at the end of the menstrual cycle also may induce menstruation; however, the cessation of progesterone secretion is the most important factor during the mature ovulatory phase of the menstrual cycle. The benefit derived from estrogen therapy in the prevention of postpartum breast engorgement must be carefully weighed against the potential increased risk of puerperal thromboembolism associated with the use of large doses of estrogens.

Mechanism of action

Chlorotrianisene binds to the estrogen receptor on various estrogen receptor bearing cells. Target cells include cells in the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins and suppress follicle-stimulating hormone (FSH) from the anterior pituitary.

TargetActionsOrganism
AEstrogen receptor alpha
agonist
Human
Absorption

Absorption following oral administration is rapid.

Volume of distribution
Not Available
Protein binding

50-80%

Metabolism

Metabolized principally in the liver, although the kidneys, gonads, and muscle tissues may be involved to some extent. The metabolic fate of the synthetic estrogens has not been fully elucidated.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Acute overdosage of large doses of oral contraceptives in chidren reportedly produces almost no toxicity except nausea and vomiting. Acute overdosage of estrogens may cause nausea, and withdrawal bleeding may occur in females.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinChlorotrianisene may decrease the anticoagulant activities of (R)-warfarin.
(S)-WarfarinChlorotrianisene may decrease the anticoagulant activities of (S)-Warfarin.
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Chlorotrianisene.
4-hydroxycoumarinChlorotrianisene may decrease the anticoagulant activities of 4-hydroxycoumarin.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Chlorotrianisene.
AbciximabChlorotrianisene may decrease the anticoagulant activities of Abciximab.
AbituzumabChlorotrianisene may increase the thrombogenic activities of Abituzumab.
AceclofenacAceclofenac may increase the thrombogenic activities of Chlorotrianisene.
AcenocoumarolChlorotrianisene may decrease the anticoagulant activities of Acenocoumarol.
Acetylsalicylic acidChlorotrianisene may decrease the anticoagulant activities of Acetylsalicylic acid.
Food Interactions
Not Available

References

Synthesis Reference

Shelton, R.S. and Van Campen, M.G. Jr.; U S . Patent 2,430,891; November 18,1947; assigned to the Wm. S. Merrell Company.

General References
Not Available
External Links
Human Metabolome Database
HMDB0014414
KEGG Drug
D00269
PubChem Compound
11289
PubChem Substance
46508811
ChemSpider
10815
ChEBI
3641
ChEMBL
CHEMBL1200761
Therapeutic Targets Database
DAP001012
PharmGKB
PA164768822
Drugs.com
Drugs.com Drug Page
Wikipedia
Chlorotrianisene
ATC Codes
G03CA06 — Chlorotrianisene

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Not Yet RecruitingTreatmentHepatocellular Carcinoma Non-resectable1
1, 2RecruitingTreatmentHepatocellular,Carcinoma1
1, 2RecruitingTreatmentPrimary Liver Carcinoma1
2CompletedTreatmentHepatocellular,Carcinoma2
2CompletedTreatmentLiver Cancer1
2CompletedTreatmentUnresectable Hepatocellular Carcinoma1
2Not Yet RecruitingTreatmentHepatocellular,Carcinoma1
2Not Yet RecruitingTreatmentPrimary Hepatocellular Carcinoma1
2RecruitingPreventionAdvanced Adult Hepatocellular Carcinoma1
2RecruitingTreatmentHepatic Carcinoma / Hepatocellular Cancer / Hepatocellular,Carcinoma1
2RecruitingTreatmentHepatocellular,Carcinoma2
2TerminatedTreatmentHepatocellular,Carcinoma1
3RecruitingTreatmentHepatocellular,Carcinoma1
3RecruitingTreatmentLiver Cancer1
3Unknown StatusTreatmentHepatocellular,Carcinoma1
4CompletedTreatmentHepatocellular,Carcinoma1
4CompletedTreatmentUnresectable Hepatocellular Carcinoma1
Not AvailableCompletedTreatmentHepatocellular,Carcinoma1
Not AvailableRecruitingTreatmentHepatocellular,Carcinoma / Transcatheter Arterial Chemoembolization1
Not AvailableRecruitingTreatmentUnresectable Hepatocellular Carcinoma1

Pharmacoeconomics

Manufacturers
  • Banner pharmacaps inc
  • Sanofi aventis us llc
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)113-114REM p.988 Shelton, R.S. and Van Campen, M.G. Jr.; U S . Patent 2,430,891; November 18,1947; assigned to the Wm. S. Merrell Company.
logP6.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000199 mg/mLALOGPS
logP5.95ALOGPS
logP5.43ChemAxon
logS-6.3ALOGPS
pKa (Strongest Basic)-4.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area27.69 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity119.17 m3·mol-1ChemAxon
Polarizability41.6 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.651
Caco-2 permeable+0.8218
P-glycoprotein substrateNon-substrate0.6283
P-glycoprotein inhibitor IInhibitor0.5266
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterNon-inhibitor0.8102
CYP450 2C9 substrateNon-substrate0.7764
CYP450 2D6 substrateNon-substrate0.8599
CYP450 3A4 substrateSubstrate0.6053
CYP450 1A2 substrateNon-inhibitor0.8094
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.923
CYP450 2C19 inhibitorInhibitor0.8994
CYP450 3A4 inhibitorInhibitor0.5072
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8625
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.6402
BiodegradationNot ready biodegradable0.9562
Rat acute toxicity1.9303 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8429
hERG inhibition (predictor II)Non-inhibitor0.8456
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0012-1495000000-9f658a59776206767e09

Taxonomy

Description
This compound 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.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Stilbenes
Sub Class
Not Available
Direct Parent
Stilbenes
Alternative Parents
Diphenylmethanes / Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / Vinyl chlorides / Chloroalkenes / Organochlorides / Hydrocarbon derivatives
Substituents
Stilbene / Diphenylmethane / Phenoxy compound / Anisole / Methoxybenzene / Phenol ether / Alkyl aryl ether / Monocyclic benzene moiety / Benzenoid / Chloroalkene
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
chloroalkene (CHEBI:3641)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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 tissu...
Gene Name
ESR1
Uniprot ID
P03372
Uniprot Name
Estrogen receptor
Molecular Weight
66215.45 Da
References
  1. Kupfer D, Bulger WH: Inactivation of the uterine estrogen receptor binding of estradiol during P-450 catalyzed metabolism of chlorotrianisene (TACE). Speculation that TACE antiestrogenic activity involves covalent binding to the estrogen receptor. FEBS Lett. 1990 Feb 12;261(1):59-62. [PubMed:2307235]
  2. Jordan VC, Gosden B: Inhibition of the uterotropic activity of estrogens and antiestrogens by the short acting antiestrogen LY117018. Endocrinology. 1983 Aug;113(2):463-8. [PubMed:6872937]
  3. Wang JY, Xu BH, Tian LJ, Wang Y: [Clinical characteristics and potential prognostic factors of breast cancer patients with liver metastases]. Zhonghua Zhong Liu Za Zhi. 2006 Aug;28(8):612-6. [PubMed:17236558]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxygen binding
Specific Function
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name
CYP19A1
Uniprot ID
P11511
Uniprot Name
Aromatase
Molecular Weight
57882.48 Da
References
  1. Adashi EY, Hsueh AJ: Estrogens augment the stimulation of ovarian aromatase activity by follicle-stimulating hormone in cultured rat granulosa cells. J Biol Chem. 1982 Jun 10;257(11):6077-83. [PubMed:6804461]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:40