Chemical Properties
Hygroscopic, white or almost white powder.
Originator
Eligard,Atrix Laboratories, Inc.
Definition
ChEBI: An oligopeptide comprising pyroglutamyl, histidyl, tryptophyl, seryl, tyrosyl, D-leucyl, leucyl, arginyl, and N-ethylprolinamide residues joined in sequence. It is a synthetic nonapeptide analogue of gonadotropin-releasi
g hormone, and is used as a subcutaneous hydrogel implant (particularly as the acetate salt) for the treatment of prostate cancer and for the suppression of gonadal sex hormone production in children with central precocious puberty.
Indications
Leuprolide is a potent LH-RH agonist for the first
several days to a few weeks after initiation of therapy,
and therefore, it initially stimulates testicular and ovarian
steroidogenesis. Because of this initial stimulation of
testosterone production, it is recommended that patients
with prostatic cancer be treated concurrently with
leuprolide and the antiandrogen flutamide (discussed
earlier). Leuprolide is generally well tolerated, with hot
flashes being the most common side effect.
Manufacturing Process
5-Oxo-L-prolyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-Larginyl-L-prolylethylamideacetate was prepared by using of Boc strategy on a
2%-crosslinking chloromethylated divinylbenzene-styrene copolymer in a the
Merrifield automatic sintesizer apparatus. 4.6 g of this resin/aminoacid
material is used for the synthesis of the desired nonapeptide. Each N-blocked
aminoacid is added in a three-fold access and allowed to couple to them,
existing aminoacid-resin ester in the usual coupling cycle. Ordinarily the
solvent used for the coupling reaction is dichloromethane or, when the
solubility of the blocked aminoacid is low, a mixture of dichloromethane and
DMF. Coupling is effected by the addition of a solution of
dicyclohexylcarbodiimide in dichloromethane at a 2.9 fold excess. The
sequence used for deprotection, neutralization and coupling of the next
aminoacid is done in a fully automatic system. In this manner, the peptide is
assembled using in turn Boc-Arg(Tos), Boc-Leu, Boc-D-Leu, Boc-Tyr(Cl2Bzl),
Boc-Ser(Bzl), Boc-Trp, Boc-His(DNP), and pGlu wherein all aminoacids are in
the L-form except in the leucine so designated. A 250 mg sample of the above
is placed in a hydrogen fluoride reaction with 250 mg vessel of anisole and
about 5 ml of anhydrous hydrogen fluoride is distilled into it. After 1 hour at
0°C, the hydrogen fluoride is removed with a stream of dry nitrogen and the
residue is taken up in 1% acetic acid. This solution is extracted with ether,
and the aqueous phase applied to a 1 time 30 cm column of a highly basic ion
exchange resin (marketed by Bio-Rad as AGl resin) in the acetate form. The
product is eluted with 0.1 N acetic acid and localized using thin-layer
chromatography (CHCl3/MeOH/32% HOAc: 120/90/40, silica gel G,
Cl2/tolidine). The product bearing solution is lyophilized, rechromatographed
on a Sephadex G-25 (marketed by Pharmacia of Uppsala, Sweden) column.
The product eluted is collected and lyophilized to yield a fluffy white solid. An
aminoacid analysis shows the expected ratio of all desired aminoacids
assembled in the above fashion.
Therapeutic Function
Antineoplastic
Synthesis
The synthesis process of Leuprorelin includes the following steps:
(1) Fmoc-Pro-HMPB-AM resin is obtained from Fmoc-Pro-OH and HMPB-AM resin with a substitution degree of 0.2mmol/g～1.2mmol/g as starting materials;
(2) The Fmoc-Pro-HMPB-AM resin was coupled one by one by Fmoc/tBu solid phase method to connect amino acids with protective groups in sequence, and the side chain fully protected leuprolide precursor peptide-HMPB-AM was synthesized Resin;
(3) Cut the side chain fully protected leuprolide precursor peptide-HMPB-AM resin to obtain the side chain fully protected leuprolide precursor peptide;
(4) Fully protected side chain leuprolide precursor peptide undergoes ethylamination to obtain side chain fully protected leuprolide;
(5) Leuprolide is fully protected on the side chain by removing the side chain protecting group to obtain the crude leuprolide peptide;
(6) The crude leuprorelin peptide is separated and purified by a high-pressure liquid phase column and lyophilized to obtain the leuprolide refined peptide.
