Identification

Name
Bazedoxifene
Accession Number
DB06401
Type
Small Molecule
Groups
Approved, Investigational
Description

Bazedoxifene is a third generation selective estrogen receptor modulator (SERM), developed by Pfizer following the completion of their takeover of Wyeth Pharmaceuticals. In late 2013, Pfizer received approval for bazedoxifene as part of the combination drug DUAVEE in the prevention (not treatment) of postmenopausal osteoporosis. It is approved in the European Union (marketed in Italy and Spain) and Japan, and is in the late phases of review by the United States' Food and Drug Administration (FDA). Bazedoxifene is yet to be approved by the FDA.

Structure
Thumb
Synonyms
  • bazedoxifene/conjugated estrogens
External IDs
TSE-424 / UNII-J70472UD3D / UNII-Q16TT9C5BK / WAY-140424 / WAY-TSE-424
Product Ingredients
IngredientUNIICASInChI Key
Bazedoxifene acetateJ70472UD3D198481-33-3OMZAMQFQZMUNTP-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
DuaveeBazedoxifene acetate (20 mg/1) + Conjugated estrogens (0.45 mg/1)Tablet, film coatedOralU.S. Pharmaceuticals2013-11-15Not applicableUs
DuaveeBazedoxifene acetate (20 mg/1) + Conjugated estrogens (0.45 mg/1)Tablet, film coatedOralU.S. Pharmaceuticals2013-11-15Not applicableUs
DuaveeBazedoxifene acetate (20 mg/1) + Conjugated estrogens (0.45 mg/1)Tablet, film coatedOralWyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.2013-10-03Not applicableUs
DuaviveBazedoxifene (20 mg) + Conjugated estrogens (0.45 mg)Tablet, multilayer, extended releaseOralPfizer Europe Ma Eeig2014-12-16Not applicableEu
DuaviveBazedoxifene (20 mg) + Conjugated estrogens (0.45 mg)Tablet, multilayer, extended releaseOralPfizer2016-12-20Not applicableCanada
International/Other Brands
Aprela / Viviant
Categories
UNII
Q16TT9C5BK
CAS number
198481-32-2
Weight
Average: 470.613
Monoisotopic: 470.256942963
Chemical Formula
C30H34N2O3
InChI Key
UCJGJABZCDBEDK-UHFFFAOYSA-N
InChI
InChI=1S/C30H34N2O3/c1-22-28-20-26(34)12-15-29(28)32(30(22)24-8-10-25(33)11-9-24)21-23-6-13-27(14-7-23)35-19-18-31-16-4-2-3-5-17-31/h6-15,20,33-34H,2-5,16-19,21H2,1H3
IUPAC Name
1-({4-[2-(azepan-1-yl)ethoxy]phenyl}methyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol
SMILES
CC1=C(N(CC2=CC=C(OCCN3CCCCCC3)C=C2)C2=C1C=C(O)C=C2)C1=CC=C(O)C=C1

Pharmacology

Indication

Investigated for use/treatment in osteoporosis and menopause.

Associated Conditions
Pharmacodynamics
Not Available
Mechanism of action

Bazedoxifene belongs to a class of compounds known as selective estrogen receptor modulators (SERMs). Bazedoxifene acts as both an oestrogen-receptor agonist and/or antagonist, depending upon the cell and tissue type and target genes. Bazedoxifene decreases bone resorption and reduces biochemical markers of bone turnover to the premenopausal range. These effects on bone remodelling lead to an increase in bone mineral density (BMD), which in turn contributes to a reduction in the risk of fractures. Bazedoxifene functions primarily as an oestrogen-receptor antagonist in uterine and breast tissues.

TargetActionsOrganism
AEstrogen receptor alpha
antagonist
agonist
Human
UEstrogen receptor betaNot AvailableHuman
Absorption

Bazedoxifene is rapidly absorbed with a tmax of approximately 2 hours and exhibits a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.

Volume of distribution

Following intravenous administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 ± 3.9 l/kg.

Protein binding

98-99%.

Metabolism

Glucuronidation is the major metabolic pathway. After peroral application, bazedoxifene is metabolized by UDP-glucuronosyltransferases (UGTs) to bazedoxifene-4'-glucuronide (M4) and bazedoxifene-5-glucuronide (M5).Little or no cytochrome P450-mediated metabolism is evident. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged active substance in plasma.

Route of elimination

The major route of elimination of radio-labelled bazedoxifene is the faeces, and less than 1% of the dose is eliminated in urine.

Half life

~30 hours.

Clearance

The apparent oral clearance of bazedoxifene is approximately 4 to 5 l/h/kg.

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
16-BromoepiandrosteroneThe serum concentration of 16-Bromoepiandrosterone can be increased when it is combined with Bazedoxifene.
19-norandrostenedioneThe serum concentration of 19-norandrostenedione can be increased when it is combined with Bazedoxifene.
5-androstenedioneThe serum concentration of 5-androstenedione can be increased when it is combined with Bazedoxifene.
AceclofenacAceclofenac may increase the thrombogenic activities of Bazedoxifene.
AdenineThe metabolism of Bazedoxifene can be decreased when combined with Adenine.
AldosteroneThe serum concentration of Aldosterone can be increased when it is combined with Bazedoxifene.
Ambroxol acefyllinateThe serum concentration of Ambroxol acefyllinate can be increased when it is combined with Bazedoxifene.
AminophyllineThe serum concentration of Aminophylline can be increased when it is combined with Bazedoxifene.
AncrodBazedoxifene may decrease the anticoagulant activities of Ancrod.
AndrostenedioneThe serum concentration of Androstenedione can be increased when it is combined with Bazedoxifene.
Food Interactions
Not Available

References

General References
  1. Gruber C, Gruber D: Bazedoxifene (Wyeth). Curr Opin Investig Drugs. 2004 Oct;5(10):1086-93. [PubMed:15535430]
  2. Miller PD, Chines AA, Christiansen C, Hoeck HC, Kendler DL, Lewiecki EM, Woodson G, Levine AB, Constantine G, Delmas PD: Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res. 2008 Apr;23(4):525-35. [PubMed:18072873]
External Links
KEGG Drug
D03062
PubChem Compound
154257
PubChem Substance
310264867
ChemSpider
135921
BindingDB
50099585
ChEBI
135947
ChEMBL
CHEMBL46740
HET
29S
Drugs.com
Drugs.com Drug Page
Wikipedia
Bazedoxifene
ATC Codes
G03CC07 — Conjugated estrogens and bazedoxifeneG03XC02 — Bazedoxifene
PDB Entries
4xi3
FDA label
Download (671 KB)
MSDS
Download (58.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedPreventionMenopause1
1Active Not RecruitingTreatmentHealthy Volunteers1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedOtherBone destruction2
1CompletedPreventionOne to five years postmenopausal1
1CompletedTreatmentMenopause2
1CompletedTreatmentOne to five years postmenopausal1
1Enrolling by InvitationTreatmentHealthy Volunteers1
1TerminatedBasic ScienceHealthy Volunteers1
1, 2Active Not RecruitingTreatmentBreast Cancer Metastatic / Metastatic Invasive Breast Cancer / Unresectable Locally Advanced Invasive Breast Cancer1
2CompletedNot AvailablePostmenopausal Osteoporosis (PMO)1
2RecruitingPreventionCancer, Breast1
2RecruitingTreatmentDisseminated Sclerosis / Menopause1
3CompletedPreventionBone destruction1
3CompletedTreatmentBone destruction / Menopause1
3CompletedTreatmentBone destruction1
4Active Not RecruitingPreventionRheumatoid Arthritis1
4CompletedNot AvailablePostmenopausal Osteoporosis (PMO)1
4CompletedPreventionBMI >30 kg/m2 / Glucose Homeostasis / Postmenopausal Syndrome1
Not AvailableActive Not RecruitingNot AvailablePostmenopausal Osteoporosis (PMO)1
Not AvailableCompletedNot AvailableBone destruction2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral
Tablet, multilayer, extended releaseOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5998402No1997-04-042017-04-04Us
US6479535No1999-05-062019-05-06Us
US7138392No1997-04-042017-04-04Us
US7683051No2007-03-102027-03-10Us
US8815934No1999-05-062019-05-06Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000564 mg/mLALOGPS
logP6.03ALOGPS
logP6.01ChemAxon
logS-5.9ALOGPS
pKa (Strongest Acidic)9.63ChemAxon
pKa (Strongest Basic)9.09ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area57.86 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity141.9 m3·mol-1ChemAxon
Polarizability54.06 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as 2-phenylindoles. These are indoles substituted at the 2-position with a phenyl group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Indoles
Direct Parent
2-phenylindoles
Alternative Parents
Phenylpyrroles / N-alkylindoles / Hydroxyindoles / 3-methylindoles / Phenoxy compounds / Phenol ethers / Azepanes / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Heteroaromatic compounds
show 4 more
Substituents
2-phenylindole / 2-phenylpyrrole / 3-alkylindole / Hydroxyindole / N-alkylindole / 3-methylindole / Phenoxy compound / Phenol ether / Phenol / 1-hydroxy-2-unsubstituted benzenoid
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
Agonist
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. Gruber C, Gruber D: Bazedoxifene (Wyeth). Curr Opin Investig Drugs. 2004 Oct;5(10):1086-93. [PubMed:15535430]
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. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR: Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005 Sep;146(9):3999-4008. Epub 2005 Jun 16. [PubMed:15961563]

Enzymes

1. UDP-glucuronosyltransferase 1A1
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
References
  1. Lusin TT, Mrhar A, Trontelj J: UGT1A1*28 polymorphism influences glucuronidation of bazedoxifene. Pharmazie. 2015 Feb;70(2):94-6. [PubMed:25997248]
  2. Shen L, Ahmad S, Park S, DeMaio W, Oganesian A, Hultin T, Scatina J, Bungay P, Chandrasekaran A: In vitro metabolism, permeability, and efflux of bazedoxifene in humans. Drug Metab Dispos. 2010 Sep;38(9):1471-9. doi: 10.1124/dmd.109.030999. Epub 2010 Jun 1. [PubMed:20516255]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A8
Uniprot ID
Q9HAW9
Uniprot Name
UDP-glucuronosyltransferase 1-8
Molecular Weight
59741.035 Da
References
  1. Shen L, Ahmad S, Park S, DeMaio W, Oganesian A, Hultin T, Scatina J, Bungay P, Chandrasekaran A: In vitro metabolism, permeability, and efflux of bazedoxifene in humans. Drug Metab Dispos. 2010 Sep;38(9):1471-9. doi: 10.1124/dmd.109.030999. Epub 2010 Jun 1. [PubMed:20516255]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein kinase c binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Isoform 2 lacks transferase activity but acts as a negative reg...
Gene Name
UGT1A10
Uniprot ID
Q9HAW8
Uniprot Name
UDP-glucuronosyltransferase 1-10
Molecular Weight
59809.075 Da
References
  1. Shen L, Ahmad S, Park S, DeMaio W, Oganesian A, Hultin T, Scatina J, Bungay P, Chandrasekaran A: In vitro metabolism, permeability, and efflux of bazedoxifene in humans. Drug Metab Dispos. 2010 Sep;38(9):1471-9. doi: 10.1124/dmd.109.030999. Epub 2010 Jun 1. [PubMed:20516255]

Drug created on March 19, 2008 10:29 / Updated on October 01, 2018 16:36