Arzoxifene: Difference between revisions

{{Short description|Chemical compound}}

{{Drugbox

| Verifiedfields = changed

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| verifiedrevid = 457819279

| IUPAC_name = 2-(4-Methoxyphenyl)-3-[4-(2-piperidin-1-ylethoxy)phenoxy]-1-benzothiophen-6-ol

| image = Arzoxifene.svg

| width = 250px

<!--Clinical data-->

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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

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| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

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| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Selective estrogen receptor modulator]]

<!--Pharmacokinetic data-->

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<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 182133-25-1

| CAS_supplemental = <br />182133-27-3 ([[hydrochloride]])

| ATC_prefix =

| ATC_suffix =

| ATC_supplemental =

| PubChem = 179337

| IUPHAR_ligand =

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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 156104

| KEGG = D02993

| ChEBI =

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 226267

| synonyms = LY-353381

<!--Chemical data-->

| C=28 | H=29 | N=1 | O=4 | S=1

| SMILES = COC1=CC=C(C=C1)C2=C(C3=C(S2)C=C(C=C3)O)OC4=CC=C(C=C4)OCCN5CCCCC5

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C28H29NO4S/c1-31-22-8-5-20(6-9-22)28-27(25-14-7-21(30)19-26(25)34-28)33-24-12-10-23(11-13-24)32-18-17-29-15-3-2-4-16-29/h5-14,19,30H,2-4,15-18H2,1H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

'''Arzoxifene''' ({{abbrlink|INN|International Nonproprietary Name}}; developmental code name '''LY-353381''') is a [[selective estrogen receptor modulator]] (SERM) of the [[benzothiophene]] group which was never marketed.<ref name="pmid17654759">{{cite journal |vauthors=Overk CR, Peng KW, Asghodom RT |title=Structure-activity relationships for a family of benzothiophene selective estrogen receptor modulators including raloxifene and arzoxifene |journal=ChemMedChem |volume=2 |issue=10 |pages=1520–6 |year=2007 |pmid=17654759 |doi=10.1002/cmdc.200700104|s2cid=35664796 |display-authors=etal}}</ref> It is a potent [[estrogen]] [[receptor antagonist|antagonist]] in mammary and uterine tissue while acting as an estrogen [[agonist]] to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the [[carcinogen]] [[nitrosomethylurea]] and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.

==Pharmacology==

Arzoxifene is a [[selective estrogen receptor modulator]] (SERM), and hence is a mixed [[agonist]] and [[receptor antagonist|antagonist]] of the [[estrogen receptor]] with [[tissue selectivity|tissue-selective]] [[estrogen (medication)|estrogen]]ic and [[antiestrogen]]ic activity.<ref name="pmid25210448">{{cite journal | vauthors = Martinkovich S, Shah D, Planey SL, Arnott JA | title = Selective estrogen receptor modulators: tissue specificity and clinical utility | journal = Clin Interv Aging | volume = 9 | pages = 1437–52 | date = 2014 | pmid = 25210448 | pmc = 4154886 | doi = 10.2147/CIA.S66690 | doi-access = free }}</ref> It has antiestrogenic effects in the [[breast]], mixed estrogenic and antiestrogenic effects in the [[uterus]], and estrogenic effects in [[bone]].<ref name="pmid25210448" /> The medication has been found to suppress [[gonadotropin]] levels in [[menopause|postmenopausal]] women, increase [[sex hormone-binding globulin]] levels, and decrease [[insulin-like growth factor 1]] and [[insulin-like growth factor-binding protein 3]] levels.<ref name="pmid25210448" />

==Research==

In a phase 3 clinical study in postmenopausal women, arzoxifene was shown to increase bone spine and hip mineral density and had no effect on the uterus and endometrium.<ref name="pmid19351734">{{cite journal | vauthors = Bolognese M, Krege JH, Utian WH, Feldman R, Broy S, Meats DL, Alam J, Lakshmanan M, Omizo M | title = Effects of arzoxifene on bone mineral density and endometrium in postmenopausal women with normal or low bone mass | journal = J. Clin. Endocrinol. Metab. | volume = 94 | issue = 7 | pages = 2284–9 |date=July 2009 | pmid = 19351734 | doi = 10.1210/jc.2008-2143 | doi-access = free }}</ref>

Lilly announced in August 2009 that preliminary results from a five-year clinical study showed that arzoxifene met its primary endpoints of reduction in vertebral fractures and breast cancer in postmenopausal women. However arzoxifene failed to meet secondary endpoints of reduction in non-vertebral fractures and cardiovascular events and improvements in cognitive function. Based on these results, Lilly announced they are discontinuing further development of the drug and would not seek regulatory approval.<ref name="Lilly_2009">{{cite web | title = Lilly Reports on Outcome of Phase III Study of Arzoxifene | url = http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=403905 | date = 2009-08-18 | work = Press Release | publisher = Eli Lilly and Company | access-date = 2009-08-24}}</ref>

A 2015 [[network meta-analysis]] found that arzoxifene significantly reduced the risk of [[breast cancer]] ({{abbrlink|RR|relative risk}} = 0.415) and to a greater extent than [[raloxifene]] ({{abbr|RR|relative risk}} = 0.572) or [[tamoxifen]] ({{abbr|RR|relative risk}} = 0.708).<ref name="pmid26582062">{{cite journal | vauthors = Mocellin S, Pilati P, Briarava M, Nitti D | title = Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials | journal = J. Natl. Cancer Inst. | volume = 108 | issue = 2 | year = 2016 | pmid = 26582062 | doi = 10.1093/jnci/djv318 | doi-access = free }}</ref>

{{Reflist|2}}

==External links==

* [http://adisinsight.springer.com/drugs/800010379 Arzoxifene - AdisInsight]

{{Estrogen receptor modulators}}

[[Category:Abandoned drugs]]

[[Category:Benzothiophenes]]

[[Category:Hydroquinone ethers]]

[[Category:2-Phenoxyethanamines]]

[[Category:Phenols]]

[[Category:1-Piperidinyl compounds]]

[[Category:Selective estrogen receptor modulators]]