Arzoxifene

Clinical data
Other names	LY-353381
Routes of administration	By mouth
Drug class	Selective estrogen receptor modulator
Identifiers
IUPAC name 2-(4-Methoxyphenyl)-3-[4-(2-piperidin-1-ylethoxy)phenoxy]-1-benzothiophen-6-ol
CAS Number	182133-25-1 Y 182133-27-3 (hydrochloride)
PubChem CID	179337
ChemSpider	156104 Y
UNII	E569WG6E60
KEGG	D02993
ChEMBL	ChEMBL226267 Y
CompTox Dashboard (EPA)	DTXSID10171255
Chemical and physical data
Formula	C28H29NO4S
Molar mass	475.60 g·mol−1
3D model (JSmol)	Interactive image
SMILES COC1=CC=C(C=C1)C2=C(C3=C(S2)C=C(C=C3)O)OC4=CC=C(C=C4)OCCN5CCCCC5
InChI 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 Y Key:MCGDSOGUHLTADD-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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.

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]