Identification

Name
Afimoxifene
Accession Number
DB04468  (EXPT02425)
Type
Small Molecule
Groups
Investigational
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
International/Other Brands
Tamogel
Categories
UNII
95K54647BZ
CAS number
68392-35-8
Weight
Average: 387.514
Monoisotopic: 387.219829177
Chemical Formula
C26H29NO2
InChI Key
TXUZVZSFRXZGTL-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
Pharmacodynamics
Not 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.

TargetActionsOrganism
UEstrogen receptor alphaNot AvailableHuman
UEstrogen receptor betaNot AvailableHuman
UEstrogen-related receptor gammaNot AvailableHuman
UTrefoil factor 1Not AvailableHuman
USteroid hormone receptor ERR1
inhibitor
Human
UNuclear receptor subfamily 1 group I member 2Not AvailableHuman
USex hormone-binding globulinNot AvailableHuman
Absorption

Absorbed following topical application.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Afimoxifene.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Afimoxifene.Experimental
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
CymarinCymarin may decrease the cardiotoxic activities of Afimoxifene.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Afimoxifene.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Afimoxifene.Approved, Investigational
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
GitoformateGitoformate may decrease the cardiotoxic activities of Afimoxifene.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Afimoxifene.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Afimoxifene.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Afimoxifene.Experimental, Investigational
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
PeruvosidePeruvoside may decrease the cardiotoxic activities of Afimoxifene.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Afimoxifene.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Afimoxifene.Approved, Investigational
Food Interactions
Not Available

References

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
Human Metabolome Database
HMDB60530
KEGG Drug
D06551
KEGG Compound
C05011
PubChem Compound
449459
PubChem Substance
175426858
ChemSpider
395987
BindingDB
20608
ChEBI
44616
ChEMBL
CHEMBL489
HET
OHT
Wikipedia
Afimoxifene
PDB Entries
1s9q / 1vjb / 2bj4 / 2fsz / 2gpu / 2gpv / 2jf9 / 2p7z / 3ert / 4q50

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentDuctal Breast Carcinoma In Situ / Estrogen Receptor-Positive Breast Cancer1
2Not Yet RecruitingPreventionMammographically Dense Breast1
2RecruitingTreatmentCancer, Breast / Metastatic Breast Adenocarcinoma1
2RecruitingTreatmentDuctal Breast Carcinoma In Situ / Estrogen Receptor Positive1
3Not Yet RecruitingTreatmentMammographic Breast Density1
Not AvailableCompletedScreeningCancer, Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not 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
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/MSsplash10-0ads-3973000000-bb1382fca99270235a01

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 / Phenylpropanes / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Trialkylamines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Stilbene / Diphenylmethane / Phenylpropane / Phenoxy compound / Phenol ether / Alkyl aryl ether / 1-hydroxy-2-unsubstituted benzenoid / Phenol / Monocyclic benzene moiety / Benzenoid
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary 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 tissu...
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 m...
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 ...
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...
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 an...
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...
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 November 09, 2017 03:42