129453-61-8 Usage
Description
Fulvestrant, also known as Faslodex, is a steroidal estrogen antagonist that is structurally based on the estradiol structure. It features a long, substituted alkyl chain attached at the 7α-position of the steroid skeleton, which distinguishes it from other estrogen receptor (ER) binders. Fulvestrant is a pure antagonist at both ERα and ERβ and acts as an ER downregulator, promoting the degradation of the receptor. It is devoid of agonist activity, unlike tamoxifen or raloxifene, and is used as an alternative to aromatase inhibitors in women who have experienced disease progression after prior antiestrogen therapy.
Uses
Used in Anticancer Applications:
Fulvestrant is employed as an antineoplastic agent, specifically for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women. It functions as an estrogen receptor antagonist, preventing estrogen-stimulated gene activation and interfering with estrogen-related processes essential for cell-cycle completion. Fulvestrant also downregulates the estrogen receptor by 80-90%, often to non-detectable levels, both in vitro and in vivo. It is particularly effective in blocking cell growth in tamoxifen-resistant breast cancer cell lines and preventing the growth of tamoxifen-resistant tumors in mice.
Used in Pharmaceutical Industry:
Fulvestrant is used as a once-monthly injectable steroidal estrogen antagonist for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following estrogen therapy. Its unique pharmacological profile allows it to be an alternative to aromatase inhibitors and provides a treatment option for patients who have had disease progression after prior antiestrogen therapy, such as tamoxifen.
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.
Originator
Astra Zeneca (UK)
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 breast
cancer
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 month
i. m. injection. Several routes for the synthesis of fulvestrant
(12) were published. One of the best routes is
depicted in the scheme. The conjugate addition of Grignard
reagent derived from bromide 130 with dienone 129 gave
adduct 131 as a mixture of 7α- and 7β-isomers in a ratio of
2.5:1 in 90-95% yield. Aromatization of the A-ring with
copper bromide/lithium bromide in acetic acid followed by
hydrolysis of the ester group provided diol 132 in 80-85%
yield. Oxidation of the side chain from sulfite to sulfone
followed by crystallization provided fulvestrant (12) in 30%
overall yield from dienone 129.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
The metabolism of fulvestrant has not been fully
evaluated, but involves combinations of a number of
possible biotransformation pathways analogous to those
of endogenous steroids. Identified metabolites (includes
17-ketone, sulphone, 3-sulphate, 3- and 17-glucuronide
metabolites) are either less active or exhibit similar
activity to fulvestrant in anti-oestrogen models.
Fulvestrant is eliminated mainly in metabolised form. The
major route of excretion is via the faeces.
References
Osborne et al. (2004), Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action; Br. J. Cancer 90 (Suppl 1):S2
Thomas et al. (2005), Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells; Endocrinology 146 624
Wardley (2002), Fulvestrant: a review of its development, pre-clinical and clinical data; Int. J. Clin. Pract. ?56 305
Castro et al. (2012),?Coumestrol has neuroprotective effects before and after cerebral ischemia in female rats; Brain Res.?1474 82
Blackburn et al. (2018),?Fulvestrant for the treatment of advanced breast cancer; Expert Rev. Anticancer Ther. 18 619
Check Digit Verification of cas no
The CAS Registry Mumber 129453-61-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,9,4,5 and 3 respectively; the second part has 2 digits, 6 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 129453-61:
(8*1)+(7*2)+(6*9)+(5*4)+(4*5)+(3*3)+(2*6)+(1*1)=138
138 % 10 = 8
So 129453-61-8 is a valid CAS Registry Number.
InChI:InChI=1/C32H47F5O3S/c1-30-17-15-26-25-12-11-24(38)21-23(25)20-22(29(26)27(30)13-14-28(30)39)10-7-5-3-2-4-6-8-18-41(40)19-9-16-31(33,34)32(35,36)37/h11-12,21-22,26-29,38-39H,2-10,13-20H2,1H3/t22?,26-,27+,28+,29-,30+,41?/m1/s1
129453-61-8Relevant articles and documents
An Efficient Regioselective Preparation of Fulvestrant
Pichandi Mohanraj, Senthil Kumar,Tulasi, Ramachar,Chidambaram Subramanian, Venkatesan
, p. 362 - 368 (2021)
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Impurity control method of fulvestrant
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Paragraph 0061-0063, (2020/09/23)
The invention belongs to the field of pharmaceutical chemicals, and relates to a fulvestrant impurity control method, which is characterized in that from the introduction of chiral carbon to the synthesis of a fulvestrant intermediate compound represented by a formula VII-1, multi-step and step-by-step control is performed on 7beta isomer impurities, so that the 7beta isomer content of the VII-1 compound is between 0.1% and 0.3%, and finally the qualified fulvestrant bulk drug with stable quality is prepared. The impurity control method is simple to operate, low in production cost and high intotal yield, and can be applied to large-scale industrial production.
Processes and intermediates for preparing fulvestrant
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Paragraph 0072-0075, (2020/05/30)
The present invention provides a method and an intermediate for preparing fulvestrant, and relates to a method for preparing fulvestrant, and an intermediate (5) of fulvestrant, and a synthetic methodthereof. The method provided by the invention can be used for obtaining high-purity fulvestrant, and is suitable for industrial mass production.