Lasofoxifeneのソースを表示

{{Short description|Chemical compound}}
{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 462089255
| IUPAC_name = (5''R'',6''S'')-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol
| image = Lasofoxifene.png
| width = 225px

<!--Clinical data-->
| tradename = Fablyn
| pregnancy_category =
| legal_status =
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Selective estrogen receptor modulator]]

<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion =
<!--Identifiers-->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 180916-16-9
| ATC_prefix = G03
| ATC_suffix = XC03
| PubChem = 216416
| ChEBI = 135938
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 187585
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 337G83N988
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 328190
| IUPHAR_ligand = 7542
| synonyms =

<!--Chemical data-->
| C=28 | H=31 | N=1 | O=2
| molecular_weight = 413.55 g/mol<br />563.64 g/mol ([[tartrate]])
| SMILES = O(c1ccc(cc1)[C@@H]4c2ccc(O)cc2CC[C@@H]4c3ccccc3)CCN5CCCC5
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GXESHMAMLJKROZ-IAPPQJPRSA-N
}}

'''Lasofoxifene''', sold under the brand name '''Fablyn''', is a [[nonsteroidal]] [[selective estrogen receptor modulator]] (SERM) which is marketed by [[Pfizer]] in [[Lithuania]] and [[Portugal]] for the prevention and treatment of [[osteoporosis]] and for the treatment of [[atrophic vaginitis|vaginal atrophy]],<ref name="pmid16916275">{{cite journal | vauthors = Gennari L, Merlotti D, Martini G, Nuti R | title = Lasofoxifene: a third-generation selective estrogen receptor modulator for the prevention and treatment of osteoporosis | journal = Expert Opinion on Investigational Drugs | volume = 15 | issue = 9 | pages = 1091–103 | date = September 2006 | pmid = 16916275 | doi = 10.1517/13543784.15.9.1091 | s2cid = 20693299 }}</ref><ref name="Drugs.com">{{Cite web|url=https://www.drugs.com/international/lasofoxifene.html|title = Fablyn (Lasofoxifene tartrate) FDA Approval Status}}</ref> and the result of an exclusive research collaboration with [[Ligand Pharmaceuticals, Inc.|Ligand Pharmaceuticals]] (LGND). It also appears to have had a statistically significant effect of reducing [[breast cancer]] in women according to a study published in The Journal of the National Cancer Institute.

==Medical uses==

===Osteoporosis===
In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5&nbsp;mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events.<ref name="pmid20169039">{{cite journal | vauthors = Gennari L, Merlotti D, Nuti R | title = Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene | journal = Clinical Interventions in Aging | volume = 5 | pages = 19–29 | year = 2010 | pmid = 20169039 | pmc = 2817938 | doi = 10.2147/cia.s6083 | doi-access = free }}</ref><ref name="Cummings_2010">{{cite journal | vauthors = Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J, Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R | title = Lasofoxifene in postmenopausal women with osteoporosis | journal = The New England Journal of Medicine | volume = 362 | issue = 8 | pages = 686–96 | date = February 2010 | pmid = 20181970 | doi = 10.1056/NEJMoa0808692 | doi-access = free }}</ref>

===Breast cancer===
In studies of breast cancer prevention, lasofoxifene showed a 79% reduction in breast cancer incidence and an 83% reduction specific incidence of [[estrogen receptor]]-positive breast cancers, which is significantly higher than reductions found with the related SERMs [[tamoxifen]] and [[raloxifene]].<ref name="Henderson2015">{{cite book|author=I. Craig Henderson|title=Breast Cancer|url=https://books.google.com/books?id=z4CECgAAQBAJ&pg=PA31|date=27 October 2015|publisher=Oxford University Press, Incorporated|isbn=978-0-19-991998-7|pages=31–}}</ref> In accordance, a [[network meta-analysis]] of SERMs for breast cancer prevention found the highest reduction in risk with lasofoxifene of all the drugs.<ref name="MocellinPilati2015">{{cite journal | vauthors = Mocellin S, Pilati P, Briarava M, Nitti D | title = Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials | journal = Journal of the National Cancer Institute | volume = 108 | issue = 2 | date = February 2016 | pmid = 26582062 | doi = 10.1093/jnci/djv318 | doi-access = free }}</ref> The reduction was even greater than that observed with [[aromatase inhibitor]]s, which have generally been found to confer a greater risk reduction than SERMs.<ref name="MocellinPilati2015" /> It also has shown promise in [[Estrogen receptor alpha|ESR1]] mutant patients with 'approximately 40% of patients harboring this mutation'.<ref>{{Cite web|url=https://www.onclive.com/web-exclusives/cristofanilli-calls-for-more-effective-options-in-esr1mutant-breast-cancer|title=Cristofanilli Calls for More Effective Options in ESR1-Mutant Breast Cancer|website=OncLive|date=4 November 2019 |language=en|access-date=2019-11-12}}</ref>

==Pharmacology==

===Pharmacodynamics===
Lasofoxifene selectively binds to both [[ERα]] and [[ERβ]] with high [[affinity (pharmacology)|affinity]].<ref name="Gennari2006">{{cite journal | vauthors = Gennari L | title = Lasofoxifene: a new type of selective estrogen receptor modulator for the treatment of osteoporosis | journal = Drugs of Today | volume = 42 | issue = 6 | pages = 355–67 | date = June 2006 | pmid = 16845439 | doi = 10.1358/dot.2006.42.6.973583 }}</ref> Its [[IC50|IC<sub>50</sub>]] for ERα (1.5 nM) is similar to that of [[estradiol]] (4.8 nM) and is at least 10-fold higher than those of tamoxifen and raloxifene.<ref name="pmid20169039" />

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

===Pharmacokinetics===
Lasofoxifene has greatly improved [[oral administration|oral]] [[bioavailability]] relative to tamoxifen and raloxifene, and this may also be involved in its greater potency.<ref name="Gennari2009">{{cite journal | vauthors = Gennari L | title = Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 13 | pages = 2209–20 | date = September 2009 | pmid = 19640205 | doi = 10.1517/14656560903127241 | s2cid = 21020484 }}</ref>

==Chemistry==
Lasofoxifene is a [[naphthalene]] derivative<ref name="Gennari2006" /> and a desmethyl dihydro analogue of [[nafoxidine]].<ref name="pmid5812203">{{cite journal | vauthors = Lednicer D, Emmert DE, Lyster SC, Duncan GW | title = Mammalian antifertility agents. VI. A novel sequence for the preparation of 1,2-disubstituted 3,4-dihydronaphthalenes | journal = Journal of Medicinal Chemistry | volume = 12 | issue = 5 | pages = 881–5 | date = September 1969 | pmid = 5812203 | doi = 10.1021/jm00305a038 }}</ref>

==History==
In September 2005, [[Pfizer]] received a [[non-approvable letter]] from the U.S. [[Food and Drug Administration]] regarding lasofoxifene (trade name Oporia), a selective estrogen receptor modulator for the prevention of osteoporosis.{{cn|date=January 2025}}

In January 2008, Ligand Pharmaceuticals, through its marketing partner, [[Pfizer]], submitted a [[new drug application|New Drug Application]] for lasofoxifene, which is expected to be marketed under the tradename Fablyn. Lasofoxifene was approved in the EU under the brand name Fablyn by the EMEA in March 2009.<ref>{{cite web | url = http://www.ema.europa.eu/humandocs/Humans/EPAR/fablyn/fablyn.htm | title = Fablyn - lasofoxifene | date = 7 August 2009 | publisher = European Medicines Agency | archive-url = https://web.archive.org/web/20100413015202/http://www.ema.europa.eu/humandocs/Humans/EPAR/fablyn/fablyn.htm |archive-date= 13 April 2010 | url-status = dead }}</ref>

==Research==
Lasofoxifene is under development by Sermonix Pharmaceuticals for the treatment of [[metastatic breast cancer]] and [[dyspareunia]] associated with [[vaginal atrophy]] in the [[United States]] and [[Europe]].<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800007522|title = Lasofoxifene - Sermonix Pharmaceuticals - AdisInsight}}</ref> It is also being researched for the potential treatment of [[ovarian cancer]].<ref name="AdisInsight" /> As of December 2017, lasofoxifene is in [[Phases of clinical research#Phase III|phase III]] [[clinical trial]]s for breast cancer and [[Phases of clinical research#Phase II|phase II]] clinical studies for dyspareunia.<ref name="AdisInsight" />

==See also==
* [[List of investigational sexual dysfunction drugs]]

==References==
{{Reflist|2}}

==External links==
* [http://adisinsight.springer.com/drugs/800007522 Lasofoxifene - AdisInsight]
* {{cite web | url = http://www.lasofoxifene.com/ | title = Reference site for lasofoxifene information | access-date = 2008-03-18 | publisher = Anakena Internet Services SL }}

{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}
{{Other sex hormones and modulators of the genital system}}

[[Category:Hormonal antineoplastic drugs]]
[[Category:Phenol ethers]]
[[Category:Hydroxyarenes]]
[[Category:1-Pyrrolidinyl compounds]]
[[Category:Tetralins]]
[[Category:Selective estrogen receptor modulators]]