Fulvestrant CAS 129453-61-8
Introduction：Basic information about Fulvestrant CAS 129453-61-8, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Fulvestrant Basic informationIndications and Usage Mechanisms of Action Pharmacokinetics Adverse reactions
| Product Name: | Fulvestrant |
| Synonyms: | (7a,17b)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol;7A,17B-[9[(4,4,5,5,5-PENTAFLUOROPENTYL)SULFINYL]NONYL]ESTRA-1,3,5(10)-TRIENE-3,17-DIOL;(7alpha,17beta)-nonyl);estra-1,3,5(10)-triene-3,17-diol,7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl);Fulvtrant;7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]- (7α,17β)-estra-1,3,5(10)-triene-3,17-diol;(7a,17b)-7-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diolFulvestrantICI 182,780;Fulvestrant for system suitability |
| CAS: | 129453-61-8 |
| MF: | C32H47F5O3S |
| MW: | 606.77 |
| EINECS: | 642-998-6 |
| Product Categories: | Nuclear Receptors;Chiral Reagents;Steroids;Sulfur & Selenium Compounds;Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitors;FASLODEX;Anti-cancer&immunity;129453-61-8;GYL;API |
| Mol File: | 129453-61-8.mol |
Fulvestrant Chemical Properties
| Melting point | 104-106°C |
| Boiling point | 674.8±55.0 °C(Predicted) |
| density | 1.201±0.06 g/cm3(Predicted) |
| storage temp. | 2-8°C |
| solubility | DMSO: >5mg/mL |
| pka | 10.27±0.70(Predicted) |
| form | powder |
| color | White |
| Stability: | Stable for 2 years as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months. |
| InChIKey | VWUXBMIQPBEWFH-WCCTWKNTSA-N |
| SMILES | [C@@]12([H])[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC3C=C(O)C=CC=3[C@@]1([H])CC[C@]1(C)[C@H](CC[C@@]21[H])O |&1:0,2,32,36,38,41,r| |
| CAS DataBase Reference | 129453-61-8(CAS DataBase Reference) |
Safety Information
| WGK Germany | 3 |
| RTECS | KG7623000 |
| HS Code | 2937230000 |
| Storage Class | 11 - Combustible Solids |
| Hazard Classifications | Aquatic Chronic 4 |
| Hazardous Substances Data | 129453-61-8(Hazardous Substances Data) |
| Indications and Usage | Fulvestrant is a muscle injection drug developed by the company AstraZeneca and is suitable for treating postmenopausal women with estrogen receptor-positive metastasized breast cancer whose condition continued to worsen despite antiestrogen treatment. Fulvestrant is the only antiestrogen drug that can be widely clinically used following unsuccessful tamoxifen treatment. This drug is a type of endocrine therapy, so it will not cause any adverse effects commonly seen in chemotherapy, giving it relatively good patient compliance. Multiple clinical trials have found that 250mg Fulvestrant is effective and consistently safe as a second line of treatment for advanced breast cancer. |
| Mechanisms of Action | Many breast cancer cells contain estrogen receptors (ER), so estrogen stimulates breast cancer growth. Fulvestrant is a steroid estrogen receptor antagonist, and its chemical structure is similar to estradiol, except that its 7α position contains a linking group. Fulvestrant is a 17β-estradiol alkylamine analogue, and it binds with, prevents, and decreases ER to inhibit the estrogen signal transduction pathway. It binds competitively with ER, has a similar affinity with ER as estrogen, and inhibits gene activation stimulated by estrogen, thus affecting necessary estrogen-related processes in cell circulation. Its fulvastans have a similar affinity with ER as estrogen and is 100 times that of tamoxifen. |
| Pharmacokinetics | Fulvestrant has a relatively poor oral bioavailability, so it is commonly injected into the muscle with lipids as excipients. In an open, random and multicenter study on postmenopausal women with advanced breast cancer, one 5ml or 2 2.5ml dosages containing 250mg were injected, and their pharmacokinetics and poisonous side effects did not differ greatly, while its blood concentration was dose-dependent and had individual differences. In the 7-day treatment period, serum LH, FSH or SBHG levels did not change significantly. This drug does not pass through the blood-brain barrier and will not cause side effects such as vasomotor symptoms. |
| Adverse reactions | Fulvestrant causes relatively fewer side effects, including brief vaginal bleeding, body odor change, and sleepwalking. There have not been any reports of effects such as vaginal dryness, weight gain, blood clotting abnormalities, thrombus formation and libido change, and characteristics such as facial flushing and sweating are not affected. A small-scale stage III clinical trial on 19 women with metastasized breast cancer who used this drug showed that its clinical efficacy was 67% and there were no serious safety issues. It showed that continuous monthly injections were crucial and that it was well-tolerated, with only slight swelling and paint at injection site, while facial flushing, uterine lining thickness, sex hormone binding globulin levels, follicle stimulating hormones levels, and luteinizing hormone levels all showed no change. |
| Description | Fulvestrant was launched in the US as a novel once monthly injectable steroidalestrogen antagonist for the treatment of hormone receptor positive metastatic breastcancer in postmenopausal women with disease progression following estrogen therapy.This 7a-alkylsulphinyl derivative of estradiol can be prepared in 10 steps from 6,7-didehydro-19-nor-testosterone by successive conjugate addition of the organocupratederived from O-protected 9-bromononan-l-o1 followed by aromatization of the resultingenone, then activation of the protected primary alcohol, substitution with 4,4,5,5,5-pentafluoropentanthiol and oxidation to the sulfoxide. Fulvestrant is the first “pure”estrogen antagonist from a novel class known as selective estrogen receptor downregulators (SERDs). It binds to the estrogen receptor (ER), with affinity close to that ofestradiol and 100 fold greater than that of tamoxifen (a partial estrogen antagonist),preventing estrogen-stimulated gene activation, thereby interfering with the estrogenrelatedprocesses essential for cell-cycle completion. Fulvestrant also appears todownregulate the ER by 80-90% often to non detectable level both in vitro and in vivo. Incomparison to tamoxifen, fulvestrant is devoid of systemic estrogenic activity, it displays nouterotrophic activity and is able to block the uterine stimulation of estradiol or tamoxifen.Furthermore, fulvestrant completely blocks the cell growth in tamoxifen-resistant breastcancer cell-lines and prevents growth of tamoxifen resistant tumor in mice. In clinical trials,it was also shown that fulvestrant is comparable to anastrozole (a third generationaromatase inhibitor) both in efficacy and tolerability in postmenopausal women withtamoxifen-resistant advanced breast cancers. |
| Chemical Properties | White or almost white powder. |
| Originator | Astra Zeneca (UK) |
| Uses | A novel steroidal estrogen antagonist reported to lack any partial agonist activity. Antineoplastic (hormonal). |
| Uses | antiestrogen |
| Definition | ChEBI: A 3-hydroxy steroid that is 17beta-estradiol in which the 7alpha hydrogen has been replaced by a nonyl group in which one of the hydrogens of the terminal methyl has been replaced by a (4,4,5,5,5-pentafluoropentyl)sulfinylgroup. An estrogen receptor antagonist, it is used in the treatment of breast cancer. |
| Brand name | Faslodex (AstraZeneca). |
| General Description | Fulvestrant, 7α-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17β-diol (Faslodex), is an antagonist structurally based onthe estradiol structure, with a long, substituted alkyl chainattached at the 7α-position of the steroid skeleton. Whenbound to the ERs, this alkyl chain induces a conformationof the receptor distinctive from that formed upon estradiolor tamoxifen binding, preventing agonist action.Fulvestrant is a pure antagonist at both ERαand ERβandan ER downregulator (stimulates degradation of the ER),completely lacking the agonist activity that is seen with tamoxifenor raloxifene. The different pharmacological profileof fulvestrant allows the use of this agent in womenwho have had disease progression after prior antiestrogentherapy (typically tamoxifen), providing an alternative toaromatase inhibitors. |
| Biological Activity | A high affinity estrogen receptor antagonist (IC 50 = 0.29 nM), devoid of any partial agonism both in vitro and in vivo . Also high affinity agonist at the membrane estrogen receptor GPR30. |
| Biochem/physiol Actions | Fulvestrant (ICI 182,780) is a selective estrogen receptor down-regulator (SERD). Fulvestrant is a high affinity estrogen receptor antagonist. IC50 = 0.29 nM. Fulvestrant is the first "pure" antiestrogen with no agonistic activity both in vitro and in vivo. |
| Clinical Use | Treatment of postmenopausal women with oestrogenreceptor-positive, locally advanced or metastatic breastcancer |
| Side effects | Side effects appear to be minimal and include several GI symptoms , headache, and hot flashes . There is no clinical evidence of uterine stimulation or laboratory evidence of stimulation of endometrial carcinoma models. Fulvestrant should not be adm inistered to women who are pregnant, who are taking antic oagulants, or who have thrombocytopenia. |
| Synthesis | Fulvestrant is administered as a once a monthi. m. injection. Several routes for the synthesis of fulvestrant(12) were published. One of the best routes isdepicted in the scheme. The conjugate addition of Grignardreagent derived from bromide 130 with dienone 129 gaveadduct 131 as a mixture of 7|á- and 7|?-isomers in a ratio of2.5:1 in 90-95% yield. Aromatization of the A-ring withcopper bromide/lithium bromide in acetic acid followed byhydrolysis of the ester group provided diol 132 in 80-85%yield. Oxidation of the side chain from sulfite to sulfonefollowed by crystallization provided fulvestrant (12) in 30%overall yield from dienone 129. |
| Metabolism | The metabolism of fulvestrant has not been fullyevaluated, but involves combinations of a number ofpossible biotransformation pathways analogous to thoseof endogenous steroids. Identified metabolites (includes17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronidemetabolites) are either less active or exhibit similaractivity to fulvestrant in anti-oestrogen models. Fulvestrant is eliminated mainly in metabolised form. Themajor route of excretion is via the faeces. |
| storage | Room temperature |
| References | [1] C K OSBORNE R I N A Wakeling. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action.[J]. British Journal of Cancer, 2004, 90 Suppl 1: S2-6. DOI:10.1038/sj.bjc.6601629 [2] P THOMAS. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells.[J]. Endocrinology, 2005, 146 2: 624-632. DOI:10.1210/en.2004-1064 [3] MD A W, MRCP. FULVESTRANT: A REVIEW OF ITS DEVELOPMENT, PRE-CLINICAL AND CLINICAL DATA[J]. International Journal of Clinical Practice, 2002, 56 4: 305-309. DOI:10.1111/j.1742-1241.2002.tb11261.x [4] CIBELE CANAL CASTRO . Coumestrol has neuroprotective effects before and after global cerebral ischemia in female rats[J]. Brain Research, 2012, 1474: Pages 82-90. DOI:10.1016/j.brainres.2012.07.025 [5] SOPHIE A BLACKBURN Kwok L C Ruth M Parks. Fulvestrant for the treatment of advanced breast cancer.[J]. Expert Review of Anticancer Therapy, 2018: 619-628. DOI:10.1080/14737140.2018.1473038 |
Fulvestrant Preparation Products And Raw materials
| Raw materials | 4,4,5,5,5-Pentafluoro-1-pentanol-->(7a,17b)-7-[9-[(4,4,5,5,5-Pentafluoropentyl)thio]nonyl]-estra-1,3,5(10)-triene-3,17-diol-->(7alpha,17beta)-17-(Acetyloxy)-7-(9-bromononyl)estr-4-en-3-one-->3-O-Methyl Fulvestrant-->(7a,17b)-7-7-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17-diol 17-acetate-->Estra-1,3,5(10)-triene-3,17-diol,7-[9-[(4,4,5,5,5-pentafluoropentyl)thio]nonyl]-,17-acetate,(7a,17b)--->Dehydronandrolone Acetate-->METHANESULFONIC ACID 4,4,5,5,5-PENTAFLUORO-PENTYL ESTER-->Nandrolone |
