Lasofoxifene

Identification

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Name
Lasofoxifene
Accession Number
DB06202
Type
Small Molecule
Groups
Approved, Investigational
Description

Lasofoxifene is a non-steroidal 3rd generation selective estrogen receptor modulator (SERM) that selectively binds to both ERα and ERβ with high affinity. It is a naphthalene derivative marketed for prevention and treatment of osteoporosis and for the treatment of vaginal atrophy. It was initially developed as Oporia by Pfizer as a treatment for postmenopausal osteoporosis and vaginal atrophy, in which were both rejected for approval by FDA. Later Fablyn was developed as a result of a research collaboration between Pfizer and Ligand Pharmaceuticals with a newly submitted New Drug Application in 2008. It gained approval by European Commission in March 2009. Ligand Pharmaceuticals signed a license agreement with Sermonix Pharmaceuticals for the development and commercialization of oral lasofoxifene in the USA.

Structure
Thumb
Synonyms
  • (-)-cis-5,6,7,8-Tetrahydro-6-phenyl-5-(p-(2-(1-pyrrolidinyl)ethoxy)phenyl)-2-naphthol
External IDs
CP-336,156
Product Ingredients
IngredientUNIICASInChI Key
Lasofoxifene hydrochlorideUEY1KQM2MR180915-85-9SFWYWKVSAHDQRB-HBYDGSNJSA-N
Lasofoxifene tartrate85X09V2GSO190791-29-8INEHJXCWEVNEDZ-LUDNRVPPSA-N
International/Other Brands
Oporia (Pfizer)
Categories
UNII
337G83N988
CAS number
180916-16-9
Weight
Average: 413.5512
Monoisotopic: 413.235479241
Chemical Formula
C28H31NO2
InChI Key
GXESHMAMLJKROZ-IAPPQJPRSA-N
InChI
InChI=1S/C28H31NO2/c30-24-11-15-27-23(20-24)10-14-26(21-6-2-1-3-7-21)28(27)22-8-12-25(13-9-22)31-19-18-29-16-4-5-17-29/h1-3,6-9,11-13,15,20,26,28,30H,4-5,10,14,16-19H2/t26-,28+/m1/s1
IUPAC Name
(5R,6S)-6-phenyl-5-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-5,6,7,8-tetrahydronaphthalen-2-ol
SMILES
[H][C@@]1(CCC2=CC(O)=CC=C2[C@@]1([H])C1=CC=C(OCCN2CCCC2)C=C1)C1=CC=CC=C1

Pharmacology

Indication

Investigated for use/treatment in postmenopausal osteoporosis to reduce the risk of both vertebral and novertebral fractures, as well as address other postmenopausal conditions, including reduction in risk of breast cancer and treatment of vulvar and vaginal atrophy (VVA)

Pharmacodynamics

Lasofoxifene exhibits both significant estrogenic and antiestrogenic activity both in vitro and in vivo, targeting any tissues that possess ERs, such as bone, uterus, breast, blood vessels, and liver. Binding assays demonstrated high affinity of the compound for both ERα and ERβ in a tissue-dependent manner. It mimics the effects of estradiol with varying agonist and antagonist effects.

Mechanism of action

Lasofoxifene mediates an agonist effect on estrogen receptors expressed on bone to mimic the positive effects of estrogen to reduce the production and lifespan of osteoclasts via altering the NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, stimulation of osteoblast (the bone forming cells) activity and additional effects on calcium homeostasis [4]. It acts as an antagonist at uterus and mammary glands [8] by suppressing the estrogen signaling in oncogenic pathways and inhibits the downstream gene transcription [9]. A study also suggests that lasofoxifene may also act as an inverse agonist at CB2 cannabinoid receptor which is expressed in bone to inhibit osteoclast formation and resorptive activity.

TargetActionsOrganism
AEstrogen receptor alpha
antagonist
agonist
negative modulator
Humans
AEstrogen receptor beta
agonist
Humans
UCannabinoid receptor 2
inverse agonist
Humans
Additional Data Available
Adverse Effects

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Additional Data Available
Contraindications

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Blackbox Warnings

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Absorption

Peak plasma concentrations (Cmax) were reached in about 6.0 to 7.3 hours [6]. Displays higher oral bioavailability compared to other SERMs with increased resistance to intestinal glucuronidation due to nonpolar tetrahydronaphthalene structure [1]. In a comparative study in the rat, lasofoxifene showed bioavailability of 62% [5].

Volume of distribution

The apparent volume of distribution in postmenopausal women is 1350L [13].

Protein binding

Lasofoxifene is highly bound to plasma proteins (>99%) where it predominantly binds to albumin and α1-acid glycoprotein [13].

Metabolism

Phase I oxidation via hepatic CYP3A4/CYP3A5 and CYP2D6 accounts for nearly half of total metabolism of lasofoxifene. Phase II conjugation reactions include glucuronidation and sulfation. Its glucuronidation is catalyzed by UGTs that are expressed in both the liver (UGT1A1, UGT1A3, UGT1A6, and UGT1A9) and the intestine (UGT1A8 and UGT1A10). Further metabolites of lasofoxifene detected in plasma are the glucuronide of a hydroxylated metabolite, and the methylated catechols [13].

Route of elimination

Primarily fecal excretion and secondarily renal elimination as mainly metabolites, with less than 2% excreted in urine as unchanged parent drug.

Half life

Elimination half-life is approximately 6 days [5].

Clearance

The apparent oral clearance (CL/F) of lasofoxifene in postmenopausal women is approximately 6.6 l/hr[13].

Toxicity

Lasofoxifene increases the risk of venous thromboembolism driven by increased risk of deep vein thrombosis. Other adverse effects include hot flushes, muscle spasms and vaginal bleeding.

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

Interactions

Drug Interactions
DrugInteraction
OspemifeneThe risk or severity of adverse effects can be increased when Lasofoxifene is combined with Ospemifene.
Additional Data Available
  • Extended Description
    Extended Description

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    Severity

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    Evidence Level

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    Evidence Level

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Food Interactions
Not Available

References

General References
  1. Gennari L, Merlotti D, Martini G, Nuti R: Lasofoxifene: a third-generation selective estrogen receptor modulator for the prevention and treatment of osteoporosis. Expert Opin Investig Drugs. 2006 Sep;15(9):1091-103. [PubMed:16916275]
  2. Crabtree JS, Peano BJ, Zhang X, Komm BS, Winneker RC, Harris HA: Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland. Mol Cell Endocrinol. 2008 Jun 11;287(1-2):40-6. doi: 10.1016/j.mce.2008.01.027. Epub 2008 Feb 12. [PubMed:18367319]
  3. Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J: The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene. Protein Sci. 2007 May;16(5):897-905. [PubMed:17456742]
  4. Gennari L, Merlotti D, Nuti R: Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene. Clin Interv Aging. 2010 Feb 2;5:19-29. [PubMed:20169039]
  5. Gennari L, Merlotti D, De Paola V, Nuti R: Lasofoxifene: Evidence of its therapeutic value in osteoporosis. Core Evid. 2010 Jun 15;4:113-29. [PubMed:20694069]
  6. Lewiecki EM: Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis. Ther Clin Risk Manag. 2009;5:817-27. Epub 2009 Nov 2. [PubMed:19898646]
  7. Nelson ER, Wardell SE, McDonnell DP: The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone. 2013 Mar;53(1):42-50. doi: 10.1016/j.bone.2012.11.011. Epub 2012 Nov 17. [PubMed:23168292]
  8. Hadji P: The evolution of selective estrogen receptor modulators in osteoporosis therapy. Climacteric. 2012 Dec;15(6):513-23. doi: 10.3109/13697137.2012.688079. Epub 2012 Aug 1. [PubMed:22853318]
  9. den Hollander P, Savage MI, Brown PH: Targeted therapy for breast cancer prevention. Front Oncol. 2013 Sep 23;3:250. doi: 10.3389/fonc.2013.00250. [PubMed:24069582]
  10. Link [Link]
  11. Fablyn development history [Link]
  12. FDA Reproductive Health Drugs Advisory Committee Briefing Document [Link]
  13. EMA Summary of product characteristics [Link]
External Links
KEGG Drug
D04672
PubChem Compound
216416
PubChem Substance
347827762
ChemSpider
187585
BindingDB
20606
ChEMBL
CHEMBL328190
HET
C3D
Drugs.com
Drugs.com Drug Page
Wikipedia
Lasofoxifene
ATC Codes
G03XC03 — Lasofoxifene
PDB Entries
2ouz

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedBasic ScienceBone Loss1
2CompletedTreatmentOsteoporosis1
2Not Yet RecruitingTreatmentLocally Advanced or Metastatic Breast Cancer1
3CompletedPreventionOsteoporosis1
3CompletedTreatmentOsteoporosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral500 μg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000398 mg/mLALOGPS
logP6.36ALOGPS
logP5.97ChemAxon
logS-6ALOGPS
pKa (Strongest Acidic)10.21ChemAxon
pKa (Strongest Basic)8.98ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area32.7 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity126.83 m3·mol-1ChemAxon
Polarizability47.58 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.7823
Blood Brain Barrier+0.5747
Caco-2 permeable-0.7333
P-glycoprotein substrateSubstrate0.8015
P-glycoprotein inhibitor INon-inhibitor0.7467
P-glycoprotein inhibitor IIInhibitor0.8219
Renal organic cation transporterNon-inhibitor0.5282
CYP450 2C9 substrateNon-substrate0.801
CYP450 2D6 substrateNon-substrate0.7939
CYP450 3A4 substrateSubstrate0.5529
CYP450 1A2 substrateNon-inhibitor0.634
CYP450 2C9 inhibitorNon-inhibitor0.8592
CYP450 2D6 inhibitorNon-inhibitor0.6456
CYP450 2C19 inhibitorNon-inhibitor0.8662
CYP450 3A4 inhibitorNon-inhibitor0.7852
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8019
Ames testNon AMES toxic0.756
CarcinogenicityNon-carcinogens0.948
BiodegradationNot ready biodegradable0.8483
Rat acute toxicity2.6029 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6526
hERG inhibition (predictor II)Inhibitor0.6914
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 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 phenylnaphthalenes. These are compounds containing a phenylnaphthalene skeleton, which consists of a naphthalene bound to a phenyl group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Naphthalenes
Sub Class
Phenylnaphthalenes
Direct Parent
Phenylnaphthalenes
Alternative Parents
Stilbenes / Tetralins / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / N-alkylpyrrolidines / Trialkylamines / Azacyclic compounds / Organopnictogen compounds
show 1 more
Substituents
Phenylnaphthalene / Stilbene / Tetralin / Phenoxy compound / Phenol ether / Alkyl aryl ether / 1-hydroxy-2-unsubstituted benzenoid / Monocyclic benzene moiety / N-alkylpyrrolidine / Pyrrolidine
show 13 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
naphthols, N-alkylpyrrolidine (CHEBI:41282)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
Agonist
Negative modulator
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. Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J: The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene. Protein Sci. 2007 May;16(5):897-905. [PubMed:17456742]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
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. Peng J, Sengupta S, Jordan VC: Potential of selective estrogen receptor modulators as treatments and preventives of breast cancer. Anticancer Agents Med Chem. 2009 Jun;9(5):481-99. [PubMed:19519291]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inverse agonist
General Function
Cannabinoid receptor activity
Specific Function
Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and b...
Gene Name
CNR2
Uniprot ID
P34972
Uniprot Name
Cannabinoid receptor 2
Molecular Weight
39680.275 Da
References
  1. Kumar P, Song ZH: CB2 cannabinoid receptor is a novel target for third-generation selective estrogen receptor modulators bazedoxifene and lasofoxifene. Biochem Biophys Res Commun. 2014 Jan 3;443(1):144-9. doi: 10.1016/j.bbrc.2013.11.071. Epub 2013 Nov 23. [PubMed:24275139]

Drug created on March 19, 2008 10:17 / Updated on April 10, 2019 13:51