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Identification
- Generic Name
- Lasofoxifene
- DrugBank Accession Number
- DB06202
- Background
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.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Lasofoxifene (DB06202)
- Weight
- Average: 413.5512
Monoisotopic: 413.235479241 - Chemical Formula
- C28H31NO2
- Synonyms
- (-)-cis-5,6,7,8-Tetrahydro-6-phenyl-5-(p-(2-(1-pyrrolidinyl)ethoxy)phenyl)-2-naphthol
- Lasofoxifene
- External IDs
- CP-336,156
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)
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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.
Target Actions Organism AFusion glycoprotein F0 modulatorHuman respiratory syncytial virus A (strain A2) AEstrogen receptor antagonistagonistnegative modulatorHumans AEstrogen receptor beta agonistHumans UCannabinoid receptor 2 inverse agonistHumans - 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.
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- 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/hr13.
- Adverse Effects
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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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareFluoroestradiol F-18 Lasofoxifene may decrease effectiveness of Fluoroestradiol F-18 as a diagnostic agent. Ospemifene The risk or severity of adverse effects can be increased when Lasofoxifene is combined with Ospemifene. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Lasofoxifene hydrochloride UEY1KQM2MR 180915-85-9 SFWYWKVSAHDQRB-HBYDGSNJSA-N Lasofoxifene tartrate 85X09V2GSO 190791-29-8 INEHJXCWEVNEDZ-LUDNRVPPSA-N - International/Other Brands
- Oporia (Pfizer)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fablyn Tablet, film coated 500 μg Oral Dr Friedrich Eberth Arzneimittel Gmb H 2016-09-07 2012-02-17 EU 
Fablyn Tablet, film coated 500 μg Oral Dr Friedrich Eberth Arzneimittel Gmb H 2016-09-07 2012-02-17 EU Fablyn Tablet, film coated 500 μg Oral Dr Friedrich Eberth Arzneimittel Gmb H 2016-09-07 2012-02-17 EU Fablyn Tablet, film coated 500 μg Oral Dr Friedrich Eberth Arzneimittel Gmb H 2016-09-07 2012-02-17 EU
Categories
- ATC Codes
- G03XC03 — Lasofoxifene
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Amine / Aromatic heteropolycyclic compound / Azacycle / Ether / Hydrocarbon derivative / Monocyclic benzene moiety / N-alkylpyrrolidine / Organic nitrogen compound show 13 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- naphthols, N-alkylpyrrolidine (CHEBI:41282)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 337G83N988
- CAS number
- 180916-16-9
- 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
References
- General References
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Lewiecki EM: Lasofoxifene for the prevention and treatment of postmenopausal osteoporosis. Ther Clin Risk Manag. 2009;5:817-27. Epub 2009 Nov 2. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Link [Link]
- Fablyn development history [Link]
- FDA Reproductive Health Drugs Advisory Committee Briefing Document [Link]
- EMA Summary of product characteristics [Link]
- External Links
- KEGG Drug
- D04672
- PubChem Compound
- 216416
- PubChem Substance
- 347827762
- ChemSpider
- 187585
- BindingDB
- 20606
- ChEMBL
- CHEMBL328190
- ZINC
- ZINC000003918428
- PDBe Ligand
- C3D
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Lasofoxifene
- PDB Entries
- 2ouz / 6vgh / 6vjd
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Completed Prevention Osteoporosis 1 somestatus stop reason just information to hide 3 Completed Treatment Osteoporosis 1 somestatus stop reason just information to hide 3 Recruiting Treatment Metastatic Breast Cancer 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Metastatic Breast Cancer 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Metastatic or Locally Advanced Breast Cancer 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, film coated Oral 500 μg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.000398 mg/mL ALOGPS logP 6.36 ALOGPS logP 5.97 Chemaxon logS -6 ALOGPS pKa (Strongest Acidic) 10.21 Chemaxon pKa (Strongest Basic) 8.98 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 32.7 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 126.83 m3·mol-1 Chemaxon Polarizability 47.58 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.7823 Blood Brain Barrier + 0.5747 Caco-2 permeable - 0.7333 P-glycoprotein substrate Substrate 0.8015 P-glycoprotein inhibitor I Non-inhibitor 0.7467 P-glycoprotein inhibitor II Inhibitor 0.8219 Renal organic cation transporter Non-inhibitor 0.5282 CYP450 2C9 substrate Non-substrate 0.801 CYP450 2D6 substrate Non-substrate 0.7939 CYP450 3A4 substrate Substrate 0.5529 CYP450 1A2 substrate Non-inhibitor 0.634 CYP450 2C9 inhibitor Non-inhibitor 0.8592 CYP450 2D6 inhibitor Non-inhibitor 0.6456 CYP450 2C19 inhibitor Non-inhibitor 0.8662 CYP450 3A4 inhibitor Non-inhibitor 0.7852 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8019 Ames test Non AMES toxic 0.756 Carcinogenicity Non-carcinogens 0.948 Biodegradation Not ready biodegradable 0.8483 Rat acute toxicity 2.6029 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6526 hERG inhibition (predictor II) Inhibitor 0.6914
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-0001900000-fc8837dd848a38138ca4 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-03di-0010900000-00158097087498ee2d4a Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-3154900000-707b7079a1899926c591 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-0093200000-06ecc3863bcb608bdce8 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-00ke-6198200000-b748c41cd238031c962d Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0m61-9221100000-3a6fce53289b7b9b7b7b Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 212.4523091 predictedDarkChem Lite v0.1.0 [M-H]- 189.43501 predictedDeepCCS 1.0 (2019) [M+H]+ 214.3856091 predictedDarkChem Lite v0.1.0 [M+H]+ 191.83057 predictedDeepCCS 1.0 (2019) [M+Na]+ 212.1039091 predictedDarkChem Lite v0.1.0 [M+Na]+ 197.74312 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Human respiratory syncytial virus A (strain A2)
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Fusion glycoprotein F0 Inactive precursor that is cleaved at two sites by a furin-like protease to give rise to the mature F1 and F2 fusion glycoproteins.
- Specific Function
- Identical protein binding
- Gene Name
- F
- Uniprot ID
- P03420
- Uniprot Name
- Fusion glycoprotein F0
- Molecular Weight
- 63452.745 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AntagonistAgonistNegative modulator
- General 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 factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032). Maintains neuronal survival in response to ischemic reperfusion injury when in the presence of circulating estradiol (17-beta-estradiol/E2) (By similarity)
- Specific Function
- 14-3-3 protein binding
- Gene Name
- ESR1
- Uniprot ID
- P03372
- Uniprot Name
- Estrogen receptor
- Molecular Weight
- 66215.45 Da
References
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1/ER-alpha, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560)
- Specific Function
- Dna binding
- Gene Name
- ESR2
- Uniprot ID
- Q92731
- Uniprot Name
- Estrogen receptor beta
- Molecular Weight
- 59215.765 Da
References
- 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. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inverse agonist
- General Function
- Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis
- Specific Function
- Cannabinoid receptor activity
- Gene Name
- CNR2
- Uniprot ID
- P34972
- Uniprot Name
- Cannabinoid receptor 2
- Molecular Weight
- 39680.275 Da
References
- 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. [Article]
Drug created at March 19, 2008 16:17 / Updated at August 26, 2024 19:24