Arzoxifene

Arzoxifene (INNTooltip International Nonproprietary Name; developmental code name LY-353381) is a selective estrogen receptor modulator (SERM) of the benzothiophene group which was never marketed.[1] It is a potent estrogen 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.

Arzoxifene
Clinical data
Other namesLY-353381
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator
Identifiers
  • 2-(4-Methoxyphenyl)-3-[4-(2-piperidin-1-ylethoxy)phenoxy]-1-benzothiophen-6-ol
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC28H29NO4S
Molar mass475.60 g·mol−1
3D model (JSmol)
  • COC1=CC=C(C=C1)C2=C(C3=C(S2)C=C(C=C3)O)OC4=CC=C(C=C4)OCCN5CCCCC5
  • InChI=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 checkY
  • Key:MCGDSOGUHLTADD-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Pharmacology

Arzoxifene is a selective estrogen receptor modulator (SERM), and hence is a mixed agonist and antagonist of the estrogen receptor with tissue-selective estrogenic and antiestrogenic activity.[2] It has antiestrogenic effects in the breast, mixed estrogenic and antiestrogenic effects in the uterus, and estrogenic effects in bone.[2] The medication has been found to suppress gonadotropin levels in postmenopausal women, increase sex hormone-binding globulin levels, and decrease insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 levels.[2]

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.[3]

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.[4]

A 2015 network meta-analysis found that arzoxifene significantly reduced the risk of breast cancer (RRTooltip relative risk = 0.415) and to a greater extent than raloxifene (RR = 0.572) or tamoxifen (RR = 0.708).[5]

References
  1. Overk CR, Peng KW, Asghodom RT, et al. (2007). "Structure-activity relationships for a family of benzothiophene selective estrogen receptor modulators including raloxifene and arzoxifene". ChemMedChem. 2 (10): 1520–6. doi:10.1002/cmdc.200700104. PMID 17654759. S2CID 35664796.
  2. Martinkovich S, Shah D, Planey SL, Arnott JA (2014). "Selective estrogen receptor modulators: tissue specificity and clinical utility". Clin Interv Aging. 9: 1437–52. doi:10.2147/CIA.S66690. PMC 4154886. PMID 25210448.
  3. Bolognese M, Krege JH, Utian WH, Feldman R, Broy S, Meats DL, Alam J, Lakshmanan M, Omizo M (July 2009). "Effects of arzoxifene on bone mineral density and endometrium in postmenopausal women with normal or low bone mass". J. Clin. Endocrinol. Metab. 94 (7): 2284–9. doi:10.1210/jc.2008-2143. PMID 19351734.
  4. "Lilly Reports on Outcome of Phase III Study of Arzoxifene". Press Release. Eli Lilly and Company. 2009-08-18. Retrieved 2009-08-24.
  5. Mocellin S, Pilati P, Briarava M, Nitti D (2016). "Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials". J. Natl. Cancer Inst. 108 (2). doi:10.1093/jnci/djv318. PMID 26582062.


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