214766-78-6 Usage
Description
Degarelix, also known as Firmagon, is a third-generation competitive and reversible gonadotropin-releasing hormone receptor (GnRHR) antagonist. It is an analog of GnRH that binds competitively and reversibly to GnRH receptors in the pituitary gland, blocking the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This results in a reduction of testosterone secretion in men, providing an effective treatment for hormone-dependent prostate cancer.
Uses
Used in Hormonally Regulated Cancer Treatment:
Degarelix is used as a therapeutic agent for the treatment of advanced hormone-dependent prostate carcinoma. It offers a more efficient suppression of gonadotropin levels and a rapid onset of beneficial effects compared to GnRH agonists, without the potential flare of the disease due to initial stimulation of the hypothalamic-pituitary-gonadal axis.
Originator
Ferring Pharmaceutical (Switzerland)
Clinical Use
Ferring launched degarelix acetate, a gonadotrophin-releasing
hormone (GnRH) antagonist, in 2009 in the U.S. for the treatment
of prostate cancer. The compound has been approved by the
E.U. for the same indication, and in the same year it was launched
in the UK and Germany. Degarelix has been developed as a
one-month or three-month sustained-release injectable formulation.
Compared to other GnRH antagonists, degarelix displays
improved aqueous solubility, longer acting effects and weaker
histamine-releasing properties.
Side effects
The most common adverse events included injection site reactions (pain, erythema, swelling, or induration), hot flashes, increased weight, and increases in serum levels of transaminases and gamma-glutamyltransferase. In addition to being contraindicated in patients with a previous hypersensitivity to degarelix, it should not be administered to women who are or may become pregnant as fetal harm can occur. Since long-term androgen deprivation therapy prolongs the QT interval, physicians should consider whether the benefits of degarelix outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure or in patients taking antiarrhythmic medications.
Synthesis
The synthesis of degarelix acetate
employed iterative peptide coupling and protection/de-protection
sequences in high yields (85–99%), and this sequence is described
in the scheme. Boc-D-alanine (21) was immobilized via MBHA
resin (Bachem) by reaction with diisopropyl carbodiimide (DIC)
and 1-hydroxybenzotriazole (HOBT). The resulting product was
treated with trifluoroacetic acid (TFA) to remove the N-Boc
protecting group to reveal amine 22. The N-terminus of 22 was
then subjected to sequential coupling and de-protection cycles
with the following protected amino acids: N-Boc-L-proline, N-a-
Boc-N6-isopropyl-N6-carbobenzoxy-L-lysine and N-Boc-L-leucine
to give 23 and 24, respectively. The N-terminus of 24 was coupled
with N-a-Boc-D-4-(Fmoc-amino)phenylalanine, followed by removal
of the Fmoc group with piperidine in DMF to give the
corresponding free aniline. The free aniline resin was then reacted
with t-butyl isocyanate to generate the corresponding t-butyl urea followed by reaction with TFA to remove the Boc group to give the
t-butyl urea amine 25. The N-terminus of 25 was coupled with
N-a-Boc-L-4-(Fmoc-amino)phenylalanine, followed by removal of
the Fmoc group with piperidine in DMF to generate the corresponding
free aniline. The free aniline was reacted with L-hydroorotic
acid, followed by reaction with TFA to liberate amine 26.
Amine 26 was then coupled with O-benzylated-N-Boc-serine,
followed by removal of the Boc group with TFA and reacting the
resulting amine with N-a-Boc-D-(3-pyridyl)alanine and subsequent
removal of the Boc group with TFA gave amine 27. Amine
27 was coupled with N-Boc-D-(4-chlorophenyl)alanine, followed
by removal of the Boc group with TFA, and the resulting amine
was then coupled with N-Boc-D-(2-naphthyl)alanine, followed by
removal of its Boc group with TFA to give 28. Acylation of 28 with
acetic anhydride followed by sequential treatment with HF and
TFA resulted in cleavage from the resin, removal of the O-benzyl
group, and conversion of the t-butyl urea to the corresponding
NH2-urea, resulting in free degarelix. Finally, treatment with acetic
acid provided degarelix acetate (V).
Drug interactions
Potentially hazardous interactions with other drugsNone known
Metabolism
Undergoes peptide hydrolysis in the hepato-biliary
system, and is mainly (70-80%) excreted as peptide
fragments in the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 214766-78-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,1,4,7,6 and 6 respectively; the second part has 2 digits, 7 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 214766-78:
(8*2)+(7*1)+(6*4)+(5*7)+(4*6)+(3*6)+(2*7)+(1*8)=146
146 % 10 = 6
So 214766-78-6 is a valid CAS Registry Number.
214766-78-6Relevant articles and documents
Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 2
Biondi, Barbara,Cabri, Walter,Formaggio, Fernando,Guryanov, Ivan,Orlandin, Andrea,Ricci, Antonio,Viola, Angelo
, p. 274 - 278 (2020)
The hydrolysis and rearrangement of the dihydroorotic (Hor) residue in the presence of bases, leading to the formation of the hydantoin (Hyd) impurity, represent one of the major problems in manufacturing of the gonadotropin-releasing hormone antagonist Degarelix. In an attempt to find efficient strategies to overcome this problem, we carried out a screening of organic bases in order to select those which afforded both the rapid Fmoc deprotection during the solid-phase synthesis and the absence of this peculiar rearrangement. Among the bases tested, only tert-butylamine did not affect the peptide molecule and was able to perform fast Fmoc removal. The use of tert-butylamine for the synthesis of Degarelix led to a product with excellent purity and yield without a detectable amount of the hydantoin impurity. Thus, we showed that tert-butylamine can be a suitable alternative to piperidine for industrial-scale production of Degarelix or other Hor-containing peptide pharmaceuticals.
Overcoming Chemical Challenges in the Solid-Phase Synthesis of High-Purity GnRH Antagonist Degarelix. Part 1.
Guryanov, Ivan,Orlandin, Andrea,Viola, Angelo,Biondi, Barbara,Badocco, Denis,Formaggio, Fernando,Ricci, Antonio,Cabri, Walter
, p. 2746 - 2753 (2019)
The highly potent, long-acting, gonadotropin-releasing hormone antagonist Degarelix is known to be very efficient for prostate cancer treatment. The synthesis of decapeptide Degarelix is complicated because of the presence in its sequence of several unnatural α-amino acids, which are prone to rearrangements and side reactions. In particular, the rearrangement of the dihydroorotic (Hor) moiety with following hydantoin formation in the presence of bases represents one of the major problems. In this study, we describe a novel chemical strategy to overcome this obstacle by the use of the corresponding p-nitrophenylalanine derivative, which is reduced on the solid support to p-aminophenylalanine and acylated with dihydroorotic acid at the end of the solid-phase synthesis. Thus, the contact of Hor with the bases required for Fmoc deprotection is completely avoided. This approach provides a superior purity of Degarelix when the synthesis is carried out in the industrial scale as well.