183552-38-7 Usage
Description
Abarelix, also known as Plenaxis, is a polypeptide compound composed of ten natural and non-natural amino acid residues in a linear sequence. It is an antagonist of the gonadotropin-releasing hormone (GnRH) receptor and was launched as an intramuscular injection for the palliative treatment of advanced symptomatic prostate cancer.
Uses
Used in Pharmaceutical Industry:
Abarelix is used as a gonad-stimulating principle antagonist (LHRH) for the hormonal therapy of prostate cancer. It modulates testosterone levels to achieve medical castration levels by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby reducing the secretion of testosterone by the testes. Abarelix is the first GnRH antagonist to reach the market and offers advantages over GnRH agonists, such as avoiding the initial surge in serum testosterone concentrations and rapid attainment of castration levels.
The recommended dosage of abarelix is 100 mg intramuscular injection on days 1, 15, and 29 of therapy, and every 4 weeks thereafter. It has been demonstrated to be effective and well-tolerated in clinical trials, with a low occurrence of immediate-onset allergic reactions and adverse events similar to comparator controls.
Originator
Praecis (US)
Manufacturing Process
Abbreviation Residue or moiety:
Nal - 3-(2-naphthyl)alaninyl
4-Cl-Phe - (4'-chlorophenyl)alaninyl
Pal - 3-(3'-pyridyl)alaninyl
Pal(N-O) - 3-(3'-pyridine-N-oxide)alaninyl
Pal(iPr) - 3-N-(2-propyl)-3'-pyridinium)alaninyl
BOC - N-t-butyoxycarbonylDCC - dicyclohexylcarbodiimide
Abarelix was synthesized by the solid phase method using an automated
synthesizer (e.g. Beckman Model 990). The amino acid residues used can be
purchased from commercial sources (e.g. Aldrich Chemical Co., Milwaukee,
Wis.), or can be produced from commercially available starting materials
according to known methods. Amino acids which are not obtained
commercially can be synthesized in a protected form for coupling, or, if
appropriate, can be coupled to form a peptide and subsequently modified to
the desired form.
For example, Boc-D-Pal(iPr) was prepared next way:
Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water
was stirred at room temperature for 4 hours. The reaction vessel was cooled
to 0°C, and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was
added. After addition was complete, the mixture was allowed to warm to room
temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane
(2 g) were added after 24 hours and again after 48 hours. The mixture was
filtered, and the precipitate was washed with ethanol (2x15 ml). The filtrate
was evaporated to yield 4.3 g of a yellow oil. Crystallization from
ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p.
182°-185°C.
Synthesis of Boc-D-Pal(N-O):
Boc-D-Pal (2.0 g, 7.5 mmole) was dissolved in 40 ml acetone and 2.48 g
(16.5 mmol) of m-chloroperbenzoic acid (MCPBA) (57-86%; purchased from
Aldrich and used as received) in 80 ml acetone was added in one portion. The
mixture was stirred at room temperature for 40 hours; a small amount of
white precipitate formed as the reaction proceeded. The precipitated was
filtered and the mother liquor evaporated to yield a white precipitate. The
combined solids were washed with ether (to remove chlorobenzoic acid) and
recrystallized from ethyl acetate/hexane. Yield: 1.7 g (80%); m.p. 155°-
157°C.
A typical coupling cycle for peptide synthesis with Boc-amino acids on a
peptide synthesizer (Beckman Model 990) was as follows:
Methylbenzyhydramine (MBHA) resin (1.18 g, 0.85 meq amino groups/g resin)
was weighed into the reaction vessel and washed with two portions of
chloroform (26 ml each). The resin was prewashed with 22% thioanisole (5
ml)/66% trifluoroacetic acid (TFA) in 14 ml dichloromethane (DCM) for 5
minutes, and then deprotected for 30 minutes with the same thioanisole/TFA
mixture. The resin was washed with three portions of chloroform (20 ml
each), two portions of 2-propanol (26 ml each) and two portions of DCM (26
ml each). The resin was neutralized with two portions of 12%
diisopropylethylamine (DIPEA) (26 ml each), and then washed with four
portions of DCM (26 ml each), followed by two portions of 1:1
DCM:dimethylformamide (DMF) (26 ml each). A solution of a Boc-protected
amino acid (2.5 mole equivalents) and 1-hydroxybenzotriazole (HOBt) (2.5
mole equivalents) was introduced as a solution in 10 ml DMF, and DCC was
added (256 mg in 6 DMF). Coupling was allowed to proceed for three hours,or overnight. Hindered residues (e.g. backbone N-methyl amino acids)required longer coupling times. The resin was washed with two 26 ml portions
of DMF, followed by two 26 ml portions of 2-propanol and then two 26 ml
portions of DCM. Completion of coupling was assessed by Kaiser's test
(ninhydrin test). If coupling is not complete, a double coupling was performed
(i.e. the resin was neutralized as above and the coupling step repeated).
When complete coupling is achieved, the cycle was repeated with the next
amino acid.
Upon completion of the synthesis, the peptide was cleaved from the resin by
treatment with liquid hydrofluoric acid (HF) for 45 minutes at 0°C. The HF was
evaporated and the peptide treated with aqueous acetic acid and lyophilized.
The crude peptide was then purified by high performance liquid
chromatography (HPLC) on a C18 column, eluting with a mixture of
acetonitrile and 0.1% TFA in water. Purified fractions (homogeneous by UV
and TLC analysis) were combined and lyophilized. Analytical HPLC was used to
determine the purity of the final product; peptides synthesized was at least
98% pure.
Check Digit Verification of cas no
The CAS Registry Mumber 183552-38-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,8,3,5,5 and 2 respectively; the second part has 2 digits, 3 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 183552-38:
(8*1)+(7*8)+(6*3)+(5*5)+(4*5)+(3*2)+(2*3)+(1*8)=147
147 % 10 = 7
So 183552-38-7 is a valid CAS Registry Number.
InChI:InChI=1/C72H95ClN14O14/c1-41(2)32-54(64(93)80-53(17-10-11-30-77-42(3)4)72(101)87-31-13-18-60(87)69(98)78-43(5)63(75)92)81-68(97)58(38-62(74)91)84-70(99)61(37-46-22-27-52(90)28-23-46)86(7)71(100)59(40-88)85-67(96)57(36-48-14-12-29-76-39-48)83-66(95)56(34-45-20-25-51(73)26-21-45)82-65(94)55(79-44(6)89)35-47-19-24-49-15-8-9-16-50(49)33-47/h8-9,12,14-16,19-29,33,39,41-43,53-61,77,88,90H,10-11,13,17-18,30-32,34-38,40H2,1-7H3,(H2,74,91)(H2,75,92)(H,78,98)(H,79,89)(H,80,93)(H,81,97)(H,82,94)(H,83,95)(H,84,99)(H,85,96)/t43-,53+,54+,55-,56-,57-,58-,59+,60+,61+/m1/s1
