Arzoxifene

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Arzoxifene

IUPAC name 2-(4-Methoxyphenyl)-3-[4-(2-piperidin-1-ylethoxy)phenoxy]-1-benzothiophen-6-ol
Identifiers
CAS number	182133-25-1^N
PubChem	179337
ChemSpider	156104^Y
ChEMBL	CHEMBL226267^Y
Jmol-3D images	Image 1
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
Properties
Molecular formula	C₂₈H₂₉NO₄S
Molar mass	475.60 g/mol
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Arzoxifene is a selective estrogen receptor modulator.^[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.

Clinical studies

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.^[2]

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.^[3]

Chemistry

Palkowitz, Alan D.; Glasebrook, Andrew L.; Thrasher, K. Jeff; Hauser, Kenneth L.; Short, Lorri L.; Phillips, D. Lynn; Muehl, Brian S.; Sato, Masahiko et al (1997). "Discovery and Synthesis of [6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]- 2-(4-hydroxyphenyl)]benzo[b]thiophene: A Novel, Highly Potent, Selective Estrogen Receptor Modulator". Journal of Medicinal Chemistry 40 (10): 1407–16. doi:10.1021/jm970167b. PMID 9154963.

References

^ 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.
^ 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.
^ "Lilly Reports on Outcome of Phase III Study of Arzoxifene". Press Release. Eli Lilly and Company. 2009-08-18. http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=403905. Retrieved 2009-08-24.

Estrogenics

Receptor

ER (α, β)	Agonists: 16α-Hydroxyestrone Alestramustine Almestrone Benzestrol Bifluranol Broparestrol Carbestrol Chlorotrianisene Cloxestradiol Dienestrol Diethylstilbestrol Diethylstilbestrol diphosphate Diosgenin Doisynoestrol DPN Epiestriol Epimestrol Eptamestrol/Etamestrol ERB-041 Equilenin Equilin Estetrol Estradiol Estradiol benzoate Estradiol butyrylacetate Estradiol cypionate Estradiol dienanthate Estradiol dipropionate Estradiol diundecyclate Estradiol diundecyclenate Estradiol enanthate Estradiol fluroate Estradiol hemisuccinate Estradiol hexahydrobenzoate Estradiol monopropionate Estradiol palmitate Estradiol pivalate Estradiol propoxyphenylpropionate Estradiol stearate Estradiol undecylate Estradiol valerate Estramustine Estramustine phosphate Estrapronicate Estrazinol Estriol Estriol succinate Estriol tripropionate Estrofurate Estromustine Estrone Estrone acetate Estrone cyanate Estrone sulfate Estrone tetraacetylglucoside Estropipate Etamestrol Ethinylestradiol Ethinylestradiol 3-isopropylsulfonate FERb 033 Fenestrel Fosfestrol Furostilbestrol Hexestrol Hexestrol diacetate Hexestrol dicaprylate Hexestrol diphosphate Hexestrol dipropionate Hydroxyestrone diacetate Mestranol Methallenestril Methestrol Methestrol dipropionate Moxestrol Nilestriol Orestrate Polyestradiol phosphate PPT Promestriene Promethoestrol Quinestradol Quinestrol β-Sitosterol WAY-200,070 Mixed (SERMs): 2-Hydroxyestrone Acolbifene Afimoxifene Arzoxifene Bazedoxifene Clomifene Clomifenoxide Cyclofenil Droloxifene Enclomifene Endoxifen Epimestrol Femarelle Fispemifene GW5638 Idoxifene Lasofoxifene Levormeloxifene Menerba Mepitiostane Miproxifene Nafoxidine Nitromifene Ormeloxifene Ospemifene Panomifene Pipendoxifene Prinaberel Raloxifene SS1010 Sivifene Tamoxifen TAS-108 Tesmilifene Tibolone Toremifene Trioxifene Y-134 Zindoxifene Zuclomifene Antagonists: Acefluranol Clometerone Delmadinone Dimepregnen Epitiostanol Fulvestrant Gestrinone ICI-164,384 Mepitiostane MPP PHTPP RU-58,668 SS1020 ZK-164,015 ZK-191,703 Note: Xenoestrogens (e.g., phytoestrogens and mycoestrogens) are not included here. For a full list of xenoestrogens, see here.

GPER	Agonists: Estradiol Fulvestrant G-1 Genistein Quercetin Tamoxifen Antagonists: G-15

Enzyme
(inhibitors)

20,22-Desmolase	22-ABC 3,3′-Dimethoxybenzidine 3-Methoxybenzidine Aminoglutethimide Cyanoketone Danazol Etomidate Trilostane

17α-Hydroxylase, 17,20-Lyase	22-ABC 22-Oxime Abiraterone Bifonazole Clotrimazole Cyanoketone Cyproterone Danazol Desogestrel Econazole Galeterone Gestrinone Isoconazole Ketoconazole L-39 Levonorgestrel Liarozole LY-207,320 MDL-27,302 Miconazole Mifepristone Norethisterone Orteronel Pioglitazone Rosiglitazone Spironolactone Stanozolol SU-10,603 Tioconazole TGF-β Troglitazone VN/87-1 YM116

3β-HSD	4-MA Azastene Cyanoketone Danazol Desogestrel Epostane Genistein Gestrinone Levonorgestrel Medroxyprogesterone Medroxyprogesterone acetate Metyrapone Norethisterone Oxymetholone Pioglitazone Rosiglitazone Trilostane Troglitazone

17β-HSD	Danazol Simvastatin

Aromatase	1,4,6-Androstatriene-3,17-dione 4-Androstene-3,6,17-trione 4-Cyclohexylaniline 4-Hydroxytestosterone 5α-DHNET Abyssinone II Aminoglutethimide Anastrozole Ascorbic acid (Vitamin C) Atamestane Bifonazole CGP-45,688 CGS-47,645 Clotrimazole DHT Difeconazole Econazole Exemestane Fadrozole Fenarimol Finrozole Formestane Imazalil Isoconazole Ketoconazole Letrozole Liarozole MEN-11066 Miconazole Minamestane Nimorazole NKS01 Norethindrone ORG-33,201 Penconazole Plomestane Prochloraz Propioconazole Pyridoglutethimide Rogletimide Rotenone Talarozole Testolactone Tioconazole Triadimefon Triadimenol Troglitazone Vorozole YM511 Zinc Note: 5α-reductase and 21-hydroxylase inhibitors also affect estrogen levels as they prevent conversion of estrogen steroid precursors to non-aromatizable metabolites.

Other

Precursors	Cholesterol 22R-Hydroxycholesterol 20α,22R-Dihydroxycholesterol Pregnenolone 17-Hydroxypregnenolone Progesterone 17-Hydroxyprogesterone Cortodoxone DHEA DHEA sulfate Androstenediol Androstenedione Testosterone

Indirect	Androgens/Antiandrogens (see here) Calcitriol (a form of Vitamin D) GnRH agonists/antagonists (see here) Gonadotropins (see here) Plasma proteins (SHBG, ABP, Albumin) Progestogens/Antiprogestins (see here) Prolactin

Procedures	Adrenalectomy Hypophysectomy Oophorectomy Orchiectomy

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