AFIMOXIFENE

Investigational

Description
Sources: http://www.businesswire.com/news/home/20040205005315/en/ASCEND-Therapeutics-Acquires-North-American-Product-Rights | https://www.ncbi.nlm.nih.gov/pubmed/11447273 | https://www.ncbi.nlm.nih.gov/pubmed/3380103

Hydroxytamoxifen (Afimoxifene) is an active metabolite of tamoxifen exerting estrogen receptor modulatory function. In addition, hydroxytamoxifen binds to regulates transcriptional activity of the estrogen-related receptor gamma. ASCEND Therapeutics, Inc. was developing TamoGel (4-hydroxytamoxifen gel) for a variety of estrogen-dependent conditions, including breast cancer, cyclic breast pain and gynecomastia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Estrogen receptor 72 Target ID: CHEMBL2093866 Sources: https://www.ncbi.nlm.nih.gov/pubmed/3380103 \| https://www.ncbi.nlm.nih.gov/pubmed/7317574 \| https://www.ncbi.nlm.nih.gov/pubmed/9806352 \| https://www.ncbi.nlm.nih.gov/pubmed/591813	Modulator 846
Estrogen-related receptor gamma 11 Target ID: CHEMBL4245 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11447273	Antagonist 2849		35.0 nM [Kd]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Breast cancer 432 Sources: http://adisinsight.springer.com/drugs/800019175	Primary		Phase II 1147	Unknown Approved Use Unknown
Mastalgia 5 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17351746	Primary		Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
3.6 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26354796/	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYTAMOXIFEN plasma	Mus musculus population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
61.5 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26354796/	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYTAMOXIFEN plasma	Mus musculus population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
31.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/26354796/	1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		HYDROXYTAMOXIFEN plasma	Mus musculus population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
4 mg 1 times / day multiple, transdermal Highest studied dose Dose: 4 mg, 1 times / day Route: transdermal Route: multiple Dose: 4 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17351746/	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: F Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17351746/	Sources: https://pubmed.ncbi.nlm.nih.gov/17351746/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 activator 150 inhibitor 2252 inducer 1087	inhibitor 2438	inhibitor 2507 substrate 1388

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2057 CYP1A2 2153 CYP1B1 32 P-gp 1741 CYP19A1 429 BCRP 910 CYP3A5 136	UGT2B15 236 CYP2C19 1119 UGT1A8 323 UGT2B7 456 CYP3A5 446 P-gp 2052 SULT1A1 37 UGT1A4 399

Drug as perpetrator

Target	Modality	Activity
BCRP 985	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 71.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 859.0	no
CYP3A4 2633	activator 342 Sources: https://www.ebi.ac.uk/chembl/g/#browse/activities/full_state/eyJsaXN0Ijp7InNldHRpbmdzX3BhdGgiOiJFU19JTkRFWEVTX05PX01BSU5fU0VBUkNILkFDVElWSVRZIiwiY3VzdG9tX3F1ZXJ5IjoidGFyZ2V0X2NoZW1ibF9pZDpDSEVNQkwzNDAiLCJ1c2VfY3VzdG9tX3F1ZXJ5Ijp0cnVlLCJzZWFyY2hfdGVybSI6IiIsInRleHRfZmlsdGVyIjoiQ0hFTUJMMTAwNDEifX0=	no
CYP19A1 430	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 7.0	yes [IC50 0.0217 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 16.0	yes [IC50 12.6585 uM]
CYP2D6 2546	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 38.0	yes [IC50 40.0297 uM]
CYP2C19 2141	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 41.0	yes [IC50 44.9141 uM]
P-gp 1932	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/15386482/	yes [IC50 7.4 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/compound/449459#section=BioAssay-Results Page: 56.0	yes [IC50 71.184 uM]
CYP1B1 93	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/12419016/	yes
CYP3A4 2633	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/11950795/	yes
CYP3A5 201	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/12419016/	yes

Drug as victim

Target	Modality	Activity
CYP2C19 1119	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
CYP2D6 1388	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
CYP3A5 446	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/15386482/	yes
SULT1A1 37	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
UGT1A4 399	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
UGT1A8 323	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
UGT2B15 236	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes
UGT2B7 456	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/22041137/	yes

PubMed

Title	Date	PubMed
Human sex hormone-binding globulin binding affinities of 125 structurally diverse chemicals and comparison with their binding to androgen receptor, estrogen receptor, and α-fetoprotein.	2015-02	25349334
Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors.	2014-10-01	25106122
Cloning of circadian rhythmic pathway genes and perturbation of oscillation patterns in endocrine disrupting chemicals (EDCs)-exposed mangrove killifish Kryptolebias marmoratus.	2014-08	24726801
4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells.	2013-07-05	23624423
Inverse antagonist activities of parabens on human oestrogen-related receptor γ (ERRγ): in vitro and in silico studies.	2013-07-01	23583298
Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells.	2013-05	23373633
Bisphenol A significantly modulates long-term depression in the hippocampus as observed by multi-electrode system.	2013	23645310
Combined effects of oestrogen receptor antagonists on in vitro vitellogenesis.	2012-05-15	22366424
Diesel exhaust particulate extracts inhibit transcription of nuclear respiratory factor-1 and cell viability in human umbilical vein endothelial cells.	2012-04	22105178
Arsenic induces functional re-expression of estrogen receptor α by demethylation of DNA in estrogen receptor-negative human breast cancer.	2012	22558281
Chemical genomics profiling of environmental chemical modulation of human nuclear receptors.	2011-08	21543282
High content imaging-based assay to classify estrogen receptor-α ligands based on defined mechanistic outcomes.	2011-05-15	21256200
High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy.	2011-02-01	21233418
Prolylcarboxypeptidase regulates proliferation, autophagy, and resistance to 4-hydroxytamoxifen-induced cytotoxicity in estrogen receptor-positive breast cancer cells.	2011-01-28	21087932
Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling.	2010-12-14	21098263
Bisphenol A impairs the double-strand break repair machinery in the germline and causes chromosome abnormalities.	2010-11-23	21059909
Olfactomedin-4 regulation by estrogen in the human endometrium requires epidermal growth factor signaling.	2010-11	21048224
Development and validation of a test for environmental estrogens: Checking xeno-estrogen activity by CXCL12 secretion in BREAST CANCER CELL LINES (CXCL-test).	2010-10	20549624
Distinction of the binding modes for human nuclear receptor ERRgamma between bisphenol A and 4-hydroxytamoxifen.	2010-08	20542892
Advantages of human hepatocyte-derived transformants expressing a series of human cytochrome p450 isoforms for genotoxicity examination.	2010-08	20507880
Optimization and prevalidation of the in vitro ERalpha CALUX method to test estrogenic and antiestrogenic activity of compounds.	2010-08	20435135
The assessment of estrogenic or anti-estrogenic activity of chemicals by the human stably transfected estrogen sensitive MELN cell line: results of test performance and transferability.	2010-08	20362049
Increased expression of enolase alpha in human breast cancer confers tamoxifen resistance in human breast cancer cells.	2010-06	19655245
Estrogen and selective estrogen receptor modulators regulate vascular endothelial growth factor and soluble vascular endothelial growth factor receptor 1 in human endometrial stromal cells.	2010-05-15	19828145
E-cadherin mediates the aggregation of breast cancer cells induced by tamoxifen and epidermal growth factor.	2010-05	19593637
Delayed activation of extracellular-signal-regulated kinase 1/2 is involved in genistein- and equol-induced cell proliferation and estrogen-receptor-alpha-mediated transcription in MCF-7 breast cancer cells.	2010-05	19427779
c-Jun activation is required for 4-hydroxytamoxifen-induced cell death in breast cancer cells.	2010-02-18	19935718
Comparison of relative binding affinities to fish and mammalian estrogen receptors: the regulatory implications.	2010-02-15	19913605
Identification of novel ER-alpha target genes in breast cancer cells: gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen.	2010-01-15	19698761
Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators.	2010-01	19901195
G protein pathway suppressor 2 (GPS2) is a transcriptional corepressor important for estrogen receptor alpha-mediated transcriptional regulation.	2009-12-25	19858209
Activation function 2 mediates dioxin-induced recruitment of estrogen receptor alpha to CYP1A1 and CYP1B1.	2009-07-24	19460354
Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation.	2009-07-01	19549922
Towards high-throughput identification of endocrine disrupting compounds with mass spectrometry.	2009-06	19233257
Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells.	2009-05	19264808
Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF.	2009-03-04	19153601
The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells.	2009-03-01	19244106
Functional identification of genes causing estrogen independence of human breast cancer cells.	2009-03	18351453
Regulation of the vascular endothelial growth factor and growth by estrogen and antiestrogens through Efp in Ishikawa endometrial carcinoma cells.	2009-02	19148513
Identification of TACC1, NOV, and PTTG1 as new candidate genes associated with endocrine therapy resistance in breast cancer.	2009-02	18984771
Potential use of an estrogen-glucocorticoid receptor chimera as a drug screen for tissue selective estrogenic activity.	2009-01	18976723
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008-12	18493746
mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels.	2008-10	19016759
Preliminary molecular dynamic simulations of the estrogen receptor alpha ligand binding domain from antagonist to apo.	2008-06	18678925
Direct evidence revealing structural elements essential for the high binding ability of bisphenol A to human estrogen-related receptor-gamma.	2008-01	18197296
Structural determination of estrogen-related receptor gamma in the presence of phenol derivative compounds.	2008-01	17964775
Human CYP2A6 is induced by estrogen via estrogen receptor.	2007-10	17646279
Promotion of breast cancer by beta-hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice.	2007-07-17	17640349
Estrogen receptor-ligand complexes measured by chip-based nanoelectrospray mass spectrometry: an approach for the screening of endocrine disruptors.	2007-05	17400923
Regulation of growth hormone signaling by selective estrogen receptor modulators occurs through suppression of protein tyrosine phosphatases.	2007-05	17272397

Patents

Sample Use Guides

In Vivo Use Guide

A phase II trial of Afimoxifene (4-hydroxytamoxifen gel) for cyclical mastalgia in premenopausal women. Premenopausal women aged at least 18 years experiencing moderate to severe symptoms were randomized to receive placebo, 2 mg, or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles.

Route of Administration: Transdermal

In Vitro Use Guide

Viability of T47D, MCF-7 and BT-474 cell lines to 4-hydroxytamoxifen was dependent of its dose, and IC50 values after 96 h of treatment were 4.2, 3.2 and 5.7 μM, respectively

Substance Class	Mixture Created by `admin` on `Mon Mar 31 18:32:14 GMT 2025` Edited by `admin` on `Mon Mar 31 18:32:14 GMT 2025`
Record UNII	17197F0KYM
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AFIMOXIFENE

Official Name

English

TAMOGEL

Preferred Name

English

4-OHT

Code

English

Z/E 4-HYDROXY TAMOXIFEN

Common Name

English

4-[1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol

Common Name

English

PHENOL, 4-(1-(4-(2-(DIMETHYLAMINO)ETHOXY)PHENYL)-2-PHENYL-1-BUTENYL)-

Common Name

English

AFIMOXIFENE [USAN]

Common Name

English

afimoxifene [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1821