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Identification
NameOspemifene
Accession NumberDB04938
TypeSmall Molecule
GroupsApproved
Description

Ospemifene is a new selective non-hormonal estrogen receptor modulator (SERM) that is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. FDA approved on February 26, 2013.

Structure
Thumb
Synonyms
2-(4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethanol
2-(P-((Z)-4-Chloro-1,2-diphenyl-1-butenyl)phenoxy)ethanol
Deamino-hydroxytoremifene
FC-1271
FC-1271a
Osphena
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Osphenatablet, film coated60 mg/1oralShionogi Inc.2013-02-26Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIB0P231ILBK
CAS number128607-22-7
WeightAverage: 378.891
Monoisotopic: 378.138657687
Chemical FormulaC24H23ClO2
InChI KeyInChIKey=LUMKNAVTFCDUIE-VHXPQNKSSA-N
InChI
InChI=1S/C24H23ClO2/c25-16-15-23(19-7-3-1-4-8-19)24(20-9-5-2-6-10-20)21-11-13-22(14-12-21)27-18-17-26/h1-14,26H,15-18H2/b24-23-
IUPAC Name
2-{4-[(1Z)-4-chloro-1,2-diphenylbut-1-en-1-yl]phenoxy}ethan-1-ol
SMILES
OCCOC1=CC=C(C=C1)C(=C(\CCCl)C1=CC=CC=C1)\C1=CC=CC=C1
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 Parents
Substituents
  • Stilbene
  • Diphenylmethane
  • Phenylpropene
  • Phenol ether
  • Alkyl aryl ether
  • Benzenoid
  • Monocyclic benzene moiety
  • Ether
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Organochloride
  • Organohalogen compound
  • Alkyl halide
  • Alkyl chloride
  • Alcohol
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationOspemifene is used for the treatment of moderate to dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.
PharmacodynamicsThe half maximal inhibitory concentration (IC50) for estrogen receptor (ER) alpha and beta are 0.8 μM and 1.7 μM, respectively. Ospemifene has potential uses in the management of osteoporosis in postmenopausal women. It interacts with osteoblasts and osteoclasts in such a way that it reduces bone turnover. It also has potential uses in the prevention of breast cancer. Studies suggest that ospemifene, in a dose-dependent manner, reduces the incidence of tumours.
Mechanism of actionOspemifene is a next generation SERM (selective estrogen receptor modulator) that selectively binds to estrogen receptors and either stimulates or blocks estrogen's activity in different tissue types. It has an agonistic effect on the endometrium.
Related Articles
AbsorptionWhen a single oral dose of ospemifene 60 mg is given to postmenopausal women under fasted conditions, the pharmacokinetic parameters are as follows: Tmax = 2 hours (range of 1 - 8 hours); Cmax = 533 ng/mL; AUC (0-inf) = 4165 ng•hr/mL. When the same aforementioned dose is given to postmenopausal women under fed conditions, the pharmacokinetic parameters are as follows: Tmax = 2.5 hours (1 - 6 hours); Cmax = 1198 ng/mL; AUC (0-inf) = 7521 ng•hr/mL. Accumulation occurs following repeated doses. Time to steady state = 9 days. Although the bioavailability of ospemifene has not been formally evaluated, it is expected to have a low bioavailability because of its lipophilic nature.
Volume of distribution

448 L

Protein binding>99% bound to serum proteins
Metabolism

Ospemifene is hepatically metabolized via CYP3A4, CYP2C9, CYP2C19, and CYP2B6. The major metabolite was 4-hydroxyospemifene, 25% of the parent compound will undergo this biotransformation. Other metabolites include 4'-hydroxy-ospemifene, <7% of the parent compound will undergo this biotransformation. In order of decreasing potency, ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6 and CYP3A4.

Route of eliminationFollowing an oral administration of ospemifene, approximately 75% and 7% of the dose was excreted in feces and urine, respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine.
Half lifeTerminal half-life = 26 hours .
Clearance

Total body clearance = 9.16 L/hr.

ToxicityAdverse reactions (≥1 percent) include: hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9972
Blood Brain Barrier+0.7095
Caco-2 permeable+0.6894
P-glycoprotein substrateNon-substrate0.587
P-glycoprotein inhibitor IInhibitor0.7541
P-glycoprotein inhibitor IIInhibitor0.5935
Renal organic cation transporterNon-inhibitor0.6587
CYP450 2C9 substrateNon-substrate0.7712
CYP450 2D6 substrateNon-substrate0.8459
CYP450 3A4 substrateNon-substrate0.5552
CYP450 1A2 substrateNon-inhibitor0.5168
CYP450 2C9 inhibitorNon-inhibitor0.7604
CYP450 2D6 inhibitorNon-inhibitor0.8754
CYP450 2C19 inhibitorInhibitor0.5512
CYP450 3A4 inhibitorNon-inhibitor0.7578
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6072
Ames testNon AMES toxic0.597
CarcinogenicityNon-carcinogens0.767
BiodegradationNot ready biodegradable0.5073
Rat acute toxicity2.3083 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5657
hERG inhibition (predictor II)Non-inhibitor0.6556
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tablet, film coatedoral60 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6245819 No2000-07-212020-07-21Us
US8236861 No2006-08-112026-08-11Us
US8470890 No2004-02-132024-02-13Us
US8642079 No2008-07-092028-07-09Us
US8772353 No2004-02-132024-02-13Us
US9241915 No2004-02-132024-02-13Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.000526 mg/mLALOGPS
logP5.7ALOGPS
logP5.56ChemAxon
logS-5.9ALOGPS
pKa (Strongest Acidic)15.1ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area29.46 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity121.68 m3·mol-1ChemAxon
Polarizability41.97 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Marja Sodervall, Maire Eloranta, Arja Kalapudas, Brian Kearton, Michael McKenzie, “METHODS FOR THE PREPARATION OF FISPEMIFENE FROM OSPEMIFENE.” U.S. Patent US20080214860, issued September 04, 2008.

US20080214860
General References
  1. Taras TL, Wurz GT, DeGregorio MW: In vitro and in vivo biologic effects of Ospemifene (FC-1271a) in breast cancer. J Steroid Biochem Mol Biol. 2001 Jun;77(4-5):271-9. [PubMed:11457665 ]
  2. Voipio SK, Komi J, Kangas L, Halonen K, DeGregorio MW, Erkkola RU: Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Maturitas. 2002 Nov 20;43(3):207-14. [PubMed:12443837 ]
  3. Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O: Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial. Menopause. 2003 Sep-Oct;10(5):433-9. [PubMed:14501605 ]
  4. Ylikorkala O, Cacciatore B, Halonen K, Lassila R, Lammintausta R, Rutanen EM, Heikkinen J, Komi J: Effects of ospemifene, a novel SERM, on vascular markers and function in healthy, postmenopausal women. Menopause. 2003 Sep-Oct;10(5):440-7. [PubMed:14501606 ]
  5. Tolonen A, Koskimies P, Turpeinen M, Uusitalo J, Lammintausta R, Pelkonen O: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013;28(3):153-61. doi: 10.1515/dmdi-2013-0016. [PubMed:23729558 ]
  6. McCall JL, DeGregorio MW: Pharmacologic evaluation of ospemifene. Expert Opin Drug Metab Toxicol. 2010 Jun;6(6):773-9. doi: 10.1517/17425255.2010.487483. [PubMed:20429673 ]
External Links
ATC CodesG03XC05
AHFS Codes
  • 68:16.12
PDB EntriesNot Available
FDA labelDownload (350 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Ospemifene.
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Ospemifene.
AtazanavirThe serum concentration of Ospemifene can be increased when it is combined with Atazanavir.
BazedoxifeneThe risk or severity of adverse effects can be increased when Bazedoxifene is combined with Ospemifene.
BexaroteneThe serum concentration of Ospemifene can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Ospemifene can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Ospemifene can be decreased when it is combined with Bosentan.
CapecitabineThe serum concentration of Ospemifene can be increased when it is combined with Capecitabine.
CeritinibThe serum concentration of Ospemifene can be increased when it is combined with Ceritinib.
ChlorotrianiseneThe risk or severity of adverse effects can be increased when Chlorotrianisene is combined with Ospemifene.
ClarithromycinThe serum concentration of Ospemifene can be increased when it is combined with Clarithromycin.
ClomifeneThe risk or severity of adverse effects can be increased when Clomifene is combined with Ospemifene.
CobicistatThe serum concentration of Ospemifene can be increased when it is combined with Cobicistat.
DabrafenibThe serum concentration of Ospemifene can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Ospemifene can be increased when it is combined with Darunavir.
DeferasiroxThe serum concentration of Ospemifene can be decreased when it is combined with Deferasirox.
DelavirdineThe serum concentration of Ospemifene can be increased when it is combined with Delavirdine.
EstradiolThe risk or severity of adverse effects can be increased when Estradiol is combined with Ospemifene.
Estrone sulfateThe risk or severity of adverse effects can be increased when Estropipate is combined with Ospemifene.
FloxuridineThe serum concentration of Ospemifene can be increased when it is combined with Floxuridine.
FluconazoleThe serum concentration of Ospemifene can be increased when it is combined with Fluconazole.
FluorouracilThe serum concentration of Ospemifene can be increased when it is combined with Fluorouracil.
GemfibrozilThe serum concentration of Ospemifene can be increased when it is combined with Gemfibrozil.
IdelalisibThe serum concentration of Ospemifene can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Ospemifene can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Ospemifene can be increased when it is combined with Itraconazole.
KetoconazoleThe serum concentration of Ospemifene can be increased when it is combined with Ketoconazole.
MitotaneThe serum concentration of Ospemifene can be decreased when it is combined with Mitotane.
NefazodoneThe serum concentration of Ospemifene can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Ospemifene can be increased when it is combined with Nelfinavir.
NicardipineThe serum concentration of Ospemifene can be increased when it is combined with Nicardipine.
PhenytoinThe metabolism of Ospemifene can be increased when combined with Phenytoin.
PosaconazoleThe serum concentration of Ospemifene can be increased when it is combined with Posaconazole.
RaloxifeneThe risk or severity of adverse effects can be increased when Raloxifene is combined with Ospemifene.
RitonavirThe serum concentration of Ospemifene can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Ospemifene can be increased when it is combined with Saquinavir.
SecobarbitalThe metabolism of Ospemifene can be increased when combined with Secobarbital.
SiltuximabThe serum concentration of Ospemifene can be decreased when it is combined with Siltuximab.
St. John's WortThe serum concentration of Ospemifene can be decreased when it is combined with St. John&#39;s Wort.
SulfadiazineThe serum concentration of Ospemifene can be increased when it is combined with Sulfadiazine.
SulfisoxazoleThe serum concentration of Ospemifene can be increased when it is combined with Sulfisoxazole.
TamoxifenThe risk or severity of adverse effects can be increased when Tamoxifen is combined with Ospemifene.
TelaprevirThe serum concentration of Ospemifene can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Ospemifene can be increased when it is combined with Telithromycin.
TocilizumabThe serum concentration of Ospemifene can be decreased when it is combined with Tocilizumab.
TolbutamideThe serum concentration of Ospemifene can be increased when it is combined with Tolbutamide.
ToremifeneThe risk or severity of adverse effects can be increased when Toremifene is combined with Ospemifene.
VoriconazoleThe serum concentration of Ospemifene can be increased when it is combined with Voriconazole.
Food Interactions
  • In general, food increased the bioavailability of ospemifene by approximately 2-3 fold.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistagonist
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
Molecular Weight:
66215.45 Da
References
  1. Komi J, Heikkinen J, Rutanen EM, Halonen K, Lammintausta R, Ylikorkala O: Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol. 2004 Mar;18(3):152-8. [PubMed:15255284 ]
  2. Wurz GT, Read KC, Marchisano-Karpman C, Gregg JP, Beckett LA, Yu Q, Degregorio MW: Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice. J Steroid Biochem Mol Biol. 2005 Nov;97(3):230-40. Epub 2005 Sep 8. [PubMed:16153821 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Tolonen A, Koskimies P, Turpeinen M, Uusitalo J, Lammintausta R, Pelkonen O: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013;28(3):153-61. doi: 10.1515/dmdi-2013-0016. [PubMed:23729558 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References
  1. Tolonen A, Koskimies P, Turpeinen M, Uusitalo J, Lammintausta R, Pelkonen O: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013;28(3):153-61. doi: 10.1515/dmdi-2013-0016. [PubMed:23729558 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
References
  1. Tolonen A, Koskimies P, Turpeinen M, Uusitalo J, Lammintausta R, Pelkonen O: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013;28(3):153-61. doi: 10.1515/dmdi-2013-0016. [PubMed:23729558 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
References
  1. Tolonen A, Koskimies P, Turpeinen M, Uusitalo J, Lammintausta R, Pelkonen O: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013;28(3):153-61. doi: 10.1515/dmdi-2013-0016. [PubMed:23729558 ]
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Drug created on October 21, 2007 16:23 / Updated on May 29, 2016 02:12