Identification
NameAfimoxifene
Accession NumberDB04468  (EXPT02425)
TypeSmall Molecule
GroupsInvestigational
Description

Afimoxifene (4-Hydroxytamoxifen, trade name TamoGel) is a new estrogen inhibitor under investigation for a variety of estrogen-dependent conditions, including cyclic breast pain and gynecomastia. TamoGel is formulated using Enhanced Hydroalcoholic Gel (EHG) Technology. This technology enables percutaneous delivery of drugs that cannot be delivered orally. It is being developed by Ascent Therapeutics.

Structure
Thumb
Synonyms
4-hydroxytamoxifen
4-monohydroxytamoxifen
4-OHT
External IDs 68047-06-3 / ICI-79280
Product Ingredients Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
TamogelNot Available
Brand mixturesNot Available
Categories
UNII95K54647BZ
CAS number68392-35-8
WeightAverage: 387.514
Monoisotopic: 387.219829177
Chemical FormulaC26H29NO2
InChI KeyTXUZVZSFRXZGTL-QPLCGJKRSA-N
InChI
InChI=1S/C26H29NO2/c1-4-25(20-8-6-5-7-9-20)26(21-10-14-23(28)15-11-21)22-12-16-24(17-13-22)29-19-18-27(2)3/h5-17,28H,4,18-19H2,1-3H3/b26-25-
IUPAC Name
4-[(1Z)-1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl]phenol
SMILES
CC\C(=C(/C1=CC=C(O)C=C1)C1=CC=C(OCCN(C)C)C=C1)C1=CC=CC=C1
Pharmacology
Indication

For the potential treatment of menstrual-cycle related mastalgia, fibrocystic breast disease, breast disease, gynecomastia and Keloid scarring.

Structured Indications Not Available
PharmacodynamicsNot Available
Mechanism of action

Afimoxifene binds to estrogen receptors (ER), inducing a conformational change in the receptor. This results in a blockage or change in the expression of estrogen dependent genes.

TargetKindPharmacological actionActionsOrganismUniProt ID
Estrogen receptor alphaProteinunknownNot AvailableHumanP03372 details
Estrogen receptor betaProteinunknownNot AvailableHumanQ92731 details
Estrogen-related receptor gammaProteinunknownNot AvailableHumanP62508 details
Trefoil factor 1ProteinunknownNot AvailableHumanP04155 details
Steroid hormone receptor ERR1Proteinunknown
inhibitor
HumanP11474 details
Nuclear receptor subfamily 1 group I member 2ProteinunknownNot AvailableHumanO75469 details
Sex hormone-binding globulinProteinunknownNot AvailableHumanP04278 details
Related Articles
Absorption

Absorbed following topical application.

Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Afimoxifene.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Afimoxifene.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Afimoxifene.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Afimoxifene.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Afimoxifene.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Afimoxifene.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Afimoxifene.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Afimoxifene.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of Afimoxifene.Experimental
OspemifeneThe risk or severity of adverse effects can be increased when Afimoxifene is combined with Ospemifene.Approved
OuabainOuabain may decrease the cardiotoxic activities of Afimoxifene.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Afimoxifene.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Afimoxifene.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Bollig A, Xu L, Thakur A, Wu J, Kuo TH, Liao JD: Regulation of intracellular calcium release and PP1alpha in a mechanism for 4-hydroxytamoxifen-induced cytotoxicity. Mol Cell Biochem. 2007 Nov;305(1-2):45-54. Epub 2007 Jul 24. [PubMed:17646931 ]
  2. Mansel R, Goyal A, Nestour EL, Masini-Eteve V, O'Connell K: A phase II trial of Afimoxifene (4-hydroxytamoxifen gel) for cyclical mastalgia in premenopausal women. Breast Cancer Res Treat. 2007 Dec;106(3):389-97. Epub 2007 Mar 10. [PubMed:17351746 ]
  3. Leblanc K, Sexton E, Parent S, Belanger G, Dery MC, Boucher V, Asselin E: Effects of 4-hydroxytamoxifen, raloxifene and ICI 182 780 on survival of uterine cancer cell lines in the presence and absence of exogenous estrogens. Int J Oncol. 2007 Feb;30(2):477-87. [PubMed:17203231 ]
  4. Cardoso CM, Almeida LM, Custodio JB: 4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition. Mitochondrion. 2002 Oct;1(6):485-95. [PubMed:16120301 ]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentDuctal Breast Carcinoma In Situ / Estrogen Receptor-Positive Breast Cancer1
2Not Yet RecruitingPreventionMammographically Dense Breast1
2Not Yet RecruitingTreatmentDuctal Breast Carcinoma In Situ / Estrogen Receptor Positive1
2RecruitingTreatmentCancer, Breast / Metastatic Breast Adenocarcinoma1
3Not Yet RecruitingTreatmentMammographic Breast Density1
Not AvailableCompletedScreeningCancer, Breast1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00303 mg/mLALOGPS
logP5.44ALOGPS
logP5.69ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)9.45ChemAxon
pKa (Strongest Basic)8.66ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area32.7 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity130.41 m3·mol-1ChemAxon
Polarizability45.22 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9936
Blood Brain Barrier-0.6271
Caco-2 permeable+0.8522
P-glycoprotein substrateSubstrate0.7715
P-glycoprotein inhibitor IInhibitor0.8359
P-glycoprotein inhibitor IIInhibitor0.5471
Renal organic cation transporterInhibitor0.6067
CYP450 2C9 substrateNon-substrate0.7876
CYP450 2D6 substrateSubstrate0.7641
CYP450 3A4 substrateSubstrate0.72
CYP450 1A2 substrateInhibitor0.7407
CYP450 2C9 inhibitorNon-inhibitor0.8685
CYP450 2D6 inhibitorInhibitor0.7958
CYP450 2C19 inhibitorNon-inhibitor0.8812
CYP450 3A4 inhibitorNon-inhibitor0.831
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6389
Ames testNon AMES toxic0.8955
CarcinogenicityNon-carcinogens0.6202
BiodegradationNot ready biodegradable0.83
Rat acute toxicity1.9661 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.6942
hERG inhibition (predictor II)Inhibitor0.6346
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , PositiveNot Available
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0ads-3973000000-bb1382fca99270235a01View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassStilbenes
Sub ClassNot Available
Direct ParentStilbenes
Alternative ParentsDiphenylmethanes / Phenylpropenes / Phenylpropanes / Phenol ethers / Phenols and derivatives / Alkyl aryl ethers / Trialkylamines / Hydrocarbon derivatives
SubstituentsStilbene / Diphenylmethane / Phenylpropene / Phenylpropane / Phenol ether / Phenol / Alkyl aryl ether / Benzenoid / Monocyclic benzene moiety / Tertiary aliphatic amine
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptorstertiary amino compound, phenols (CHEBI:44616 )

Targets

Kind
Protein
Organism
Human
Pharmacological action
unknown
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 tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription fact...
Gene Name:
ESR1
Uniprot ID:
P03372
Uniprot Name:
Estrogen receptor
Molecular Weight:
66215.45 Da
References
  1. Reed CA, Berndtson AK, Nephew KP: Dose-dependent effects of 4-hydroxytamoxifen, the active metabolite of tamoxifen, on estrogen receptor-alpha expression in the rat uterus. Anticancer Drugs. 2005 Jun;16(5):559-67. [PubMed:15846122 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by...
Gene Name:
ESR2
Uniprot ID:
Q92731
Uniprot Name:
Estrogen receptor beta
Molecular Weight:
59215.765 Da
References
  1. Reed CA, Berndtson AK, Nephew KP: Dose-dependent effects of 4-hydroxytamoxifen, the active metabolite of tamoxifen, on estrogen receptor-alpha expression in the rat uterus. Anticancer Drugs. 2005 Jun;16(5):559-67. [PubMed:15846122 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Zinc ion binding
Specific Function:
Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity). Induces the expression of PERM1 in the skeletal muscle.
Gene Name:
ESRRG
Uniprot ID:
P62508
Uniprot Name:
Estrogen-related receptor gamma
Molecular Weight:
51305.485 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Stabilizer of the mucous gel overlying the gastrointestinal mucosa that provides a physical barrier against various noxious agents. May inhibit the growth of calcium oxalate crystals in urine.
Specific Function:
Growth factor activity
Gene Name:
TFF1
Uniprot ID:
P04155
Uniprot Name:
Trefoil factor 1
Molecular Weight:
9149.435 Da
References
  1. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ: Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem. 2004 Feb 6;279(6):5025-34. Epub 2003 Nov 14. [PubMed:14617632 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alp...
Gene Name:
ESRRA
Uniprot ID:
P11474
Uniprot Name:
Steroid hormone receptor ERR1
Molecular Weight:
45509.11 Da
References
  1. Huppunen J, Aarnisalo P: Dimerization modulates the activity of the orphan nuclear receptor ERRgamma. Biochem Biophys Res Commun. 2004 Feb 20;314(4):964-70. [PubMed:14751226 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and is...
Gene Name:
NR1I2
Uniprot ID:
O75469
Uniprot Name:
Nuclear receptor subfamily 1 group I member 2
Molecular Weight:
49761.245 Da
References
  1. Kretschmer XC, Baldwin WS: CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact. 2005 Aug 15;155(3):111-28. [PubMed:16054614 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Androgen binding
Specific Function:
Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone, and 17-beta-estradiol. Regulates the plasma metabolic clearance rate of steroid hormones by controlling their plasma concentration.
Gene Name:
SHBG
Uniprot ID:
P04278
Uniprot Name:
Sex hormone-binding globulin
Molecular Weight:
43778.755 Da
References
  1. Hong H, Branham WS, Ng HW, Moland CL, Dial SL, Fang H, Perkins R, Sheehan D, Tong W: Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and alpha-fetoprotein. Toxicol Sci. 2015 Feb;143(2):333-48. doi: 10.1093/toxsci/kfu231. Epub 2014 Oct 27. [PubMed:25349334 ]
Drug created on June 13, 2005 07:24 / Updated on September 01, 2017 11:17