Fulvestrant Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
Fulvestrant was launched in the US as a novel 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.
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 organocuprate
derived from O-protected 9-bromononan-l-o1 followed by aromatization of the resulting
enone, 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 down
regulators (SERDs). It binds to the estrogen receptor (ER), with affinity close to that of
estradiol and 100 fold greater than that of tamoxifen (a partial estrogen antagonist),
preventing estrogen-stimulated gene activation, thereby interfering with the estrogenrelated
processes essential for cell-cycle completion. Fulvestrant also appears to
downregulate the ER by 80-90% often to non detectable level both in vitro and in vivo. In
comparison to tamoxifen, fulvestrant is devoid of systemic estrogenic activity, it displays no
uterotrophic activity and is able to block the uterine stimulation of estradiol or tamoxifen.
Furthermore, fulvestrant completely blocks the cell growth in tamoxifen-resistant breast
cancer 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 generation
aromatase inhibitor) both in efficacy and tolerability in postmenopausal women with
tamoxifen-resistant advanced breast cancers.
Chemische Eigenschaften
White or almost white powder.
Verwenden
A novel steroidal estrogen antagonist reported to lack any partial agonist activity. Antineoplastic (hormonal).
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ChEBI: A 3-hydroxy steroid that is 17beta-estradiol in which the 7alpha hydrogen has been replaced by a nonyl group in which one of the hydrogens of the terminal methyl has been replaced by a (4,4,5,5,5-pentafluoropentyl)sulfinyl
group. An estrogen receptor antagonist, it is used in the treatment of breast cancer.
Allgemeine Beschreibung
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 ER
αand ER
βandan 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.
Biologische Aktivit?t
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.
Nebenwirkungen
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.
Fulvestrant Upstream-Materialien And Downstream Produkte
Upstream-Materialien
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
Nandrolon
Downstream Produkte
