Raloxifene

Summary

Raloxifene (CHEMBL81) is an approved small-molecule bone density conservation agent (ATC G03XC01) targeting GPER1, AOX1, and ESR1; indicated across 13 conditions including polycystic ovary syndrome and postmenopausal osteoporosis.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: G03XC01
• Targets: 4 (GPER1, AOX1, ESR1…)
• Indications: 13 conditions
• Clinical trials: 55
• Chemistry: 473.6 Da · C28H27NO4S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL81
Name	Raloxifene
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	5035
ChEBI	CHEBI:8772
ATC	G03XC01
Molecular formula	C28H27NO4S
Molecular weight	473.6
InChIKey	GZUITABIAKMVPG-UHFFFAOYSA-N

SMILES: C1CCN(CC1)CCOC2=CC=C(C=C2)C(=O)C3=C(SC4=C3C=CC(=C4)O)C5=CC=C(C=C5)O

IUPAC name: [6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone

ChEBI definition: A member of the class of 1-benzothiophenes that is 1-benzothiophene in which the hydrogens at positions 2, 3, and 6 have been replaced by p-hydroxyphenyl, p-[2-(piperidin-1-yl)ethoxy]benzoyl, and hydroxy groups, respectively.

Pharmacological roles (ChEBI): bone density conservation agent, estrogen receptor modulator, estrogen antagonist.

Also known as: Eviden, J22.982B, Keoxifene, LY-139481, NSC-747974, Raloxifene, Raloxifeno, Raloxiphene, Raxeto, raloxifene, SID11111733, SID11111734

Parent form; salt/anhydrous children: CHEMBL1116

Patent coverage: 18,759 distinct patent families (78,049 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 78,045 (100%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
GPER1	GPER	Full agonist	7	0.2%	Q99527
AOX1	aldehyde oxidase 1	Inhibition	7.35	0%	Q06278
ESR1	Estrogen receptor-α	Agonist	9.5	1.7%	P03372
ESR2	Estrogen receptor-β	Antagonist	8	0.2%	Q92731

Broader ChEMBL bioactivity targets: 76 (assay-derived). Sample: Tyrosyl-DNA phosphodiesterase 1, Microtubule-associated protein tau, Ubiquitin carboxyl-terminal hydrolase 2, Nuclear receptor ROR-gamma, Prelamin-A/C, ATP-dependent DNA helicase Q1, Thrombopoietin, Aldehyde oxidase 1, Aldehyde oxidase 1, Aldehyde oxidase 1.

Bioactivity

ChEMBL activities: 209 potent at pChembl ≥ 5 of 245 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
ESR1	10.52	Ki	0.03	nM	CHEMBL_ACT_1608726
ESR1	9.8	Ki	0.16	nM	CHEMBL_ACT_7819519
ESR1	9.74	IC50	0.18	nM	CHEMBL_ACT_19211882
ESR1	9.7	IC50	0.2	nM	CHEMBL_ACT_1054228
ESR1	9.7	IC50	0.2	nM	CHEMBL_ACT_1130490
ESR1	9.7	IC50	0.2	nM	CHEMBL_ACT_148589
ESR1	9.7	IC50	0.2	nM	CHEMBL_ACT_433162
ESR1	9.66	Ki	0.22	nM	CHEMBL_ACT_285977
ESR1	9.52	IC50	0.3	nM	CHEMBL_ACT_3424191
ESR1	9.47	IC50	0.34	nM	CHEMBL_ACT_1299460
ESR1	9.43	Ki	0.37	nM	CHEMBL_ACT_10939214
ESR1	9.42	Ki	0.38	nM	CHEMBL_ACT_10939228
ESR1	9.4	Ki	0.4	nM	CHEMBL_ACT_148587
ESR1	9.37	Ki	0.43	nM	CHEMBL_ACT_16450044
ESR1	9.34	IC50	0.46	nM	CHEMBL_ACT_2551541
ESR1	9.33	IC50	0.47	nM	CHEMBL_ACT_16588392
ESR1	9.26	IC50	0.55	nM	CHEMBL_ACT_7819518
ESR1	9.18	EC50	0.66	nM	CHEMBL_ACT_19211889
P06211	9.15	IC50	0.7	nM	CHEMBL_ACT_1157543
ESR1	9.15	IC50	0.7	nM	CHEMBL_ACT_519293
ESR1	9.14	IC50	0.73	nM	CHEMBL_ACT_1425879
ESR1	9.14	IC50	0.72	nM	CHEMBL_ACT_993613
ESR1	9.13	IC50	0.74	nM	CHEMBL_ACT_24751371
ESR1	9.1	IC50	0.8	nM	CHEMBL_ACT_1437052
ESR2	9.1	AC50	0.8	nM	CHEMBL_ACT_25175286
AOX1	9.06	Ki	0.87	nM	CHEMBL_ACT_15459136
AOX1	9.06	Ki	0.87	nM	CHEMBL_ACT_24342107
AOX1	9.06	Ki	0.87	nM	CHEMBL_ACT_24342108
AOX1	9.06	Ki	0.87	nM	CHEMBL_ACT_24342109
ESR1	9.05	IC50	0.89	nM	CHEMBL_ACT_1523959

Target pathways

Aggregated over 4 target gene(s): GPER1, AOX1, ESR1, ESR2.

Top Reactome pathways

24 total, by targets touching each:

Pathway	Targets	Genes
PIP3 activates AKT signaling	2	ESR1, ESR2
Constitutive Signaling by Aberrant PI3K in Cancer	2	ESR1, ESR2
Nuclear Receptor transcription pathway	2	ESR1, ESR2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	ESR1, ESR2
ESR-mediated signaling	2	ESR1, ESR2
Extra-nuclear estrogen signaling	2	ESR1, ESR2
Nuclear signaling by ERBB4	1	ESR1
Metabolism	1	AOX1
Metabolism of water-soluble vitamins and cofactors	1	AOX1
Metabolism of vitamins and cofactors	1	AOX1
Peptide ligand-binding receptors	1	GPER1
SUMOylation of intracellular receptors	1	ESR1
G alpha (i) signalling events	1	GPER1
Ovarian tumor domain proteases	1	ESR1
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	ESR1
RUNX1 regulates estrogen receptor mediated transcription	1	ESR1
RUNX1 regulates transcription of genes involved in WNT signaling	1	ESR1
Regulation of RUNX2 expression and activity	1	ESR1
Estrogen-dependent gene expression	1	ESR1
GPER1 signaling	1	GPER1
Vitamin B6 activation to pyridoxal phosphate	1	AOX1
Mitochondrial unfolded protein response (UPRmt)	1	ESR1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	ESR1
Developmental Lineage of Mammary Gland Alveolar Cells	1	ESR1

Dominant GO biological processes

GO term	Targets
positive regulation of transcription by RNA polymerase II	3
cellular response to estradiol stimulus	3
signal transduction	3
positive regulation of cytosolic calcium ion concentration	2
negative regulation of gene expression	2
nuclear receptor-mediated steroid hormone signaling pathway	2
steroid hormone receptor signaling pathway	2
negative regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
estrogen receptor signaling pathway	2
positive regulation of DNA-templated transcription	2
obsolete positive regulation of DNA-binding transcription factor activity	2
cellular response to oxygen-containing compound	2
positive regulation of protein phosphorylation	1

Indications & clinical

Indications

13 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
polycystic ovary syndrome	3	MONDO:0008487	EFO:0000660
postmenopausal osteoporosis	3	MONDO:0008159	EFO:0003854
osteoporosis	3	MONDO:0005298	EFO:0003882
schizoaffective disorder	3	MONDO:0005487	EFO:0005411
breast neoplasm	3	MONDO:0021100	MONDO:0007254
endometrium neoplasm	2	MONDO:0021251	MONDO:0011962
severe acute respiratory syndrome	2	MONDO:0005091	EFO:0000694
Alzheimer disease	2	MONDO:0004975	MONDO:0004975
prostate adenocarcinoma	0	MONDO:0005082	EFO:0000673

4 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 55.

Phase distribution

Phase	Trials
PHASE4	15
PHASE3	12
Not specified	11
PHASE2	9
PHASE1	5
PHASE2/PHASE3	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03623633	PHASE4	ACTIVE_NOT_RECRUITING	Comparative Antiresorptive Efficacy Discontinuation of Denosumab
NCT00030147	PHASE4	COMPLETED	Raloxifene and Rimostil for Perimenopause-Related Depression
NCT00079924	PHASE4	COMPLETED	Effects of Teriparatide in Postmenopausal Women With Osteoporosis
NCT00108238	PHASE4	COMPLETED	Estrogen Alternatives Study
NCT00191425	PHASE4	COMPLETED	2-Year Therapy With Teriparatide vs 1-yr Therapy Followed by 1-Year of Raloxifene or Calcium/Vit D in Severe Postmenopausal Osteoporosis
NCT00371956	PHASE4	COMPLETED	Raloxifene for Prevention of Bone Loss in Postmenopausal Patients Receiving Chronic Corticosteroid Therapy
NCT00431444	PHASE4	COMPLETED	Effects of Zoledronic Acid and Raloxifene on Bone Turnover Markers in Postmenopausal Women With Low Bone Mineral Density
NCT00532246	PHASE4	COMPLETED	Carotid Artery Intima-Media Thickness Following Exposure to Raloxifene or Placebo
NCT00532428	PHASE4	COMPLETED	Long Term Effects of Raloxifene Treatment on Bone Quality
NCT00790101	PHASE4	TERMINATED	Risedronate vs Raloxifene in Hormone Replacement Therapy Discontinuation
NCT01041092	PHASE4	COMPLETED	Double Blind, Placebo-controlled Study of Raloxifene for Negative Symptoms of Schizophrenia in Postmenopausal Women
NCT01166958	PHASE4	COMPLETED	Enhancing Osteoporosis Therapy: Can We Open the Anabolic Window?
NCT01535027	PHASE4	COMPLETED	Combined Administration of Teripapartide and Antiresorptive Agents in Postmenopausal Osteoporosis
NCT01544894	PHASE4	COMPLETED	Clinical Study of Raloxifene and Strontium Ranelate in Postmenopausal Osteoporosis
NCT03006003	PHASE4	UNKNOWN	Osteoporosis Treatment in Post-menopausal Women
NCT00003906	PHASE3	COMPLETED	Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer in Postmenopausal Women
NCT00046137	PHASE3	COMPLETED	Combined Use of Teriparatide and Raloxifene in Postmenopausal Women With Osteoporosis
NCT00065767	PHASE2/PHASE3	COMPLETED	Cognitive and Neurophysiological Effects of Raloxifene in Alzheimer’s Disease
NCT00163137	PHASE3	COMPLETED	Comparison of Raloxifene and Lasofoxifene - A Randomized, Blinded Study of These Drugs and Placebo on Bone Loss
NCT00190593	PHASE3	COMPLETED	Raloxifene Use for The Heart
NCT00310531	PHASE3	COMPLETED	3-year Study of Menostar Versus Evista to Prevent Osteoporosis in Post-menopausal Women
NCT00383422	PHASE3	COMPLETED	Study Comparing Arzoxifene With Raloxifene in Women After Menopause With Osteoporosis
NCT00427700	PHASE3	COMPLETED	Induction of Ovulation With Raloxifene or Clomiphene Citrate in Polycystic Ovarian Syndrome
NCT00675688	PHASE3	COMPLETED	Study Evaluating Safety and Efficacy of Bazedoxifene/Conjugated Estrogens Combinations in Postmenopausal Women
NCT00687102	PHASE3	COMPLETED	Cognition in the Study of Tamoxifen and Raloxifene
NCT01280305	PHASE3	UNKNOWN	Raloxifene in Treatment of Schizophrenia and Schizoaffective Disorder
NCT01573637	PHASE3	COMPLETED	Raloxifene as an Adjuvant Treatment of the Negative Symptoms of Schizophrenia in Post-menopausal Women
NCT03043820	PHASE3	COMPLETED	Raloxifene Augmentation in Patients With a Schizophrenia Spectrum Disorder
NCT05172050	PHASE2/PHASE3	COMPLETED	Multicenter Double Blind, Parallel-group Phase 2/3 Trial, to Study Raloxifene in Adult COVID-19 Patients.
NCT06944145	PHASE2	RECRUITING	New Treatment Strategies and Epigenetic Biomarker for Management of Benign Prostatic Hyperplasia
NCT07470606	PHASE2	NOT_YET_RECRUITING	Memantine +/- Raloxifene for Cognitive Preservation After Radiation Therapy to the Brain
NCT00001848	PHASE2	COMPLETED	The Safety and Effectiveness of Surgery With or Without Raloxifene for the Treatment of Pelvic Pain Caused by Endometriosis
NCT00004915	PHASE2	COMPLETED	Raloxifene in Treating Patients With Persistent or Recurrent Endometrial Cancer
NCT00019500	PHASE2	COMPLETED	Raloxifene in Preventing Breast Cancer in Premenopausal Women
NCT00149604	PHASE2	COMPLETED	AFTER: Altering Fat Through Estrogen and Raloxifene
NCT00206557	PHASE2	COMPLETED	The Use of Selective Estrogen Receptor Modulators in the Treatment of Schizophrenia- a Pilot Study
NCT00332553	PHASE2	COMPLETED	Study of Hot Flashes and Night Sweats in Postmenopausal Women Receiving Combination Raloxifene and Oral Estrogen
NCT00368459	PHASE2	COMPLETED	Raloxifene for Women With Alzheimer’s Disease
NCT02654093	PHASE1	COMPLETED	A Drug-drug Interaction Study of DP-R213
NCT02762643	PHASE1	COMPLETED	DP-R213 Pharmacokinetics Study

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 6 clinical and 22 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

198 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
ESTRADIOL	ChEMBL + PubChem	Phase 4 (approved)	AOX1, ESR1, ESR2, GPER1
Tamoxifen	ChEMBL + PubChem	Phase 4 (approved)	AOX1, ESR1, ESR2, GPER1
DIETHYLSTILBESTROL	ChEMBL + PubChem	Phase 4 (approved)	AOX1, ESR1, ESR2
ETHINYL ESTRADIOL	ChEMBL + PubChem	Phase 4 (approved)	AOX1, ESR1, ESR2
Fulvestrant	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2, GPER1
GENISTEIN	ChEMBL + PubChem	Phase 2 (approved)	AOX1, ESR1, ESR2
BAZEDOXIFENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
BITHIONOL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
CISPLATIN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ELACESTRANT	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTETROL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTRIOL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTRONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
HEXACHLOROPHENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
LASOFOXIFENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
MEDROXYPROGESTERONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
MIFEPRISTONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
PHENOLPHTHALEIN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
SPIRONOLACTONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ACOLBIFENE	ChEMBL	Phase 3	ESR1, ESR2
AFIMOXIFENE	ChEMBL	Phase 3	ESR1, ESR2
AMCENESTRANT	ChEMBL	Phase 3	ESR1, ESR2
ARZOXIFENE	ChEMBL	Phase 3	ESR1, ESR2
BENSERAZIDE	ChEMBL	Phase 3	ESR1, ESR2
PYRIDOXAL	ChEMBL	Phase 3	AOX1, ESR1
ALFATRADIOL	ChEMBL	Phase 2	ESR1, ESR2
AUS-131	ChEMBL	Phase 2	ESR1, ESR2
BRILANESTRANT	ChEMBL	Phase 2	ESR1, ESR2
DAIDZEIN	ChEMBL	Phase 2	ESR1, ESR2
ERTEBEREL	ChEMBL	Phase 2	ESR1, ESR2
GTX-758	ChEMBL	Phase 2	ESR1, ESR2
IDOXIFENE	ChEMBL	Phase 2	ESR1, ESR2
LEVORMELOXIFENE	ChEMBL	Phase 2	ESR1, ESR2
MOXESTROL	ChEMBL	Phase 2	ESR1, ESR2
PIPENDOXIFENE	ChEMBL	Phase 2	ESR1, ESR2
PRINABEREL	ChEMBL	Phase 2	ESR1, ESR2
STALLIMYCIN	ChEMBL	Phase 2	ESR1, ESR2
Bosentan	PubChem	Approved	ESR1, ESR2
Dihydroergotamine	PubChem	Approved	ESR1, ESR2
Fidaxomicin	PubChem	Approved	ESR1, ESR2
Propoxyphene	PubChem	Approved	ESR1, ESR2
Pyrazinamide	PubChem	Approved	ESR1, ESR2
CHLORPROMAZINE	ChEMBL + PubChem	Phase 4 (approved)	AOX1
CLOZAPINE	ChEMBL + PubChem	Phase 4 (approved)	AOX1
DOMPERIDONE	ChEMBL + PubChem	Phase 4 (approved)	AOX1
HYDRALAZINE	ChEMBL + PubChem	Phase 4 (approved)	AOX1
MENADIONE	ChEMBL + PubChem	Phase 4 (approved)	AOX1
PERPHENAZINE	ChEMBL + PubChem	Phase 4 (approved)	AOX1
ZALEPLON	ChEMBL + PubChem	Phase 4 (approved)	AOX1
ACETOPHENAZINE	ChEMBL	Phase 4 (approved)	ESR1
ALECTINIB	ChEMBL	Phase 4 (approved)	ESR1
AMSACRINE	ChEMBL	Phase 4 (approved)	AOX1
APOMORPHINE	ChEMBL	Phase 4 (approved)	ESR1
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	ESR1
ASPIRIN	ChEMBL	Phase 4 (approved)	ESR1
AZTREONAM	ChEMBL	Phase 4 (approved)	ESR1
BELINOSTAT	ChEMBL	Phase 4 (approved)	ESR1
BENZBROMARONE	ChEMBL	Phase 4 (approved)	ESR1
BEXAROTENE	ChEMBL	Phase 4 (approved)	ESR1
BISACODYL	ChEMBL	Phase 4 (approved)	ESR1