74381-53-6/Leuprorelin

Anti-cancer drugs

Leuprolide acetate is a commonly used hormone anti-cancer drug, , it is a acetate of leuprolide which is a nonapeptide synthetic analogue of LHRH( one kind decapeptide), it is a LH-RH antagonist, LHRH is produced by the hypothalamus, it can promote pituitary for the release of gonadotropins and follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This product’s structure is similar to LHRH, its acting on the anterior pituitary which prompts FSH, LH release function, increases serum concentrations of testosterone and dihydro testosterone. It is used as maintenance therapy for advanced prostate cancer clinically, but in about one week after use of the product, the number of active receptors will be reduced, and gonadotropin secretion will be reduced.After 2 to 4 weeks, the concentration of testosterone and dihydro testosterone can be reduced to castration levels. After the withdrawal, gonadotropin and androgen concentrations can be recovered to normal. Note that this product is not effective when administered orally, subcutaneous or intramuscular administration has good absorption. T1/2 of parenteral administration is 3 h. There is no accumulation in the body, unchanged drugs and its metabolites in urine excretion rates are2.9% and 1.5%, respectively. Ethanol can enhance the role of this product, the course of treatment should not drink, in case it is difficult to control the incidence of adverse reactions. In the first week of the course of treatment ,patients should try to be hospitalized for monitoring, choose an experienced physician to guide treatment to prevent severe neurological complications, urinary tract obstruction. Injection site should often vary.

Description

Leuprolide acetate is a potent analog of LH-RH useful in achieving a medical castration in the treatment of advanced prostate cancer. It has also been investigated for the treatment of advanced breast cancer.

Chemical Properties

Fluffy Solid

Originator

Takeda (Japan)

Uses

Leuprolide acetate USP (Leupron) is used to treat Prostatic carcinoma.

Definition

ChEBI: An acetate salt obtained by combining the nonapeptide leuprolide with acetic acid. A long lasting GnRH analog, LH-Rh agonist. It is a synthetic nonapeptide analogue of gonadotropin-releasing hormone, and is used as a subcutaneous hydrogel implant for the t eatment of prostate cancer and for the suppression of gonadal sex hormone production in children with central precocious puberty.

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.

Brand name

Eligard (QLT); Lupron(TAP); Viadur (ALZA);CARCINIL.

Therapeutic Function

Antineoplastic

Biochem/physiol Actions

Glp-His-Trp-Ser-Tyr-Leu-Leu-Arg-Pro-NHEt (des-Gly10-[D-Leu6]-LH-RH) is a GnRH (gonadotropin-releasing hormone) agonist, leuprolide. GnRH (Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), which is also referred as LHRH (luteinizing hormone-releasing hormone) or gonadorelin, is crucial for mammalian reproduction and is released from hypothalamic neurons. It is responsible for the secretion of gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the pituitary glands. Mutations in GnRH are associated with normosmic congenital hypogonadotropic hypogonadism. Low concentration of leuprolide can be used for the treatment of endometriosis, uterine fibroids, central precocious puberty and advanced prostate cancer.

Pharmacology

Leuprolide, 5-oxo-L-prolyl-L-histadyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucil-L-leucil-L-arginyl-N-ethyl-L-prolinamide (30.5.9), is made synthetically. pyroGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt The nonapeptide leuprolide is a synthetic analog of the decapeptide, gonadotropin releasing hormone, and it exceeds the activity of the natural hormone and significantly elevates the level of testosterone and dihydrotestosterone in men, and estrogen in women. It also inhibits follicle-stimulating hormone and leutenizing hormone. Leuprolide is used for prostate cancer, when orchiectomy or estrogen therapy is counterproductive to the patient. A synonym of this drug is lupron.

Clinical Use

Leuprolide acetate, a synthetic nonapeptide analogue of GnRH that possesses greater potency than the natural hormone, is a superagonist that is commercially available. Note that leuprolide acetate contains substitutions that hinder enzymatic degradation, D-Leu and NH-Et in place of Gly6 and Gly10-NH2, respectively. Leuprolide acetate is reportedly 15-fold the potency of natural GnRH. When given continuously and in therapeutic doses, leuprolide acetate inhibits LH and FSH secretion by desensitizing/downregulating the GnRH receptors. After an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis. In premenopausal females, estrogens are reduced to postmenopausal levels; in males, testosterone is reduced to castrate levels.Leuprolide acetate is administered by daily injections or as depot injections every month, every 3 months, every 4 months, or every 6 months as a palliative treatment in advanced prostatic carcinoma (as an alternative to orchiectomy). An implant version (Viadur) also is available for long-term palliative therapy; after implantation of the device into the upper arm, leuprolide acetate is continuously released over a 12-month period. Because dihydrotestosterone, a metabolite of testosterone, is able to stimulate the growth of prostate cancer, the ability of leuprolide acetate to bring testosterone to near castrate levels is why this drug finds use as a palliative in the advanced disease. The addition of a nonpeptidyl antiandrogen, such as flutamide or bicalutamide, to the leuprolide acetate regimen inhibits adrenal and testicular synthesized androgens from binding to or being taken up by target prostate cancer tissue. This combination therapy helps to control the initial flare-up, by blocking all sources of androgen, and is referred to as maximal androgen blockade.Leuprolide acetate, in monthly and every-3-months depot formulations, is useful in treating women diagnosed with endometriosis, but not for longer than six months because of the chance of developing osteoporosis.Central precocious puberty that is idiopathic, or gonadotropin dependent, can cause the development of secondary sexual characteristics in girls before the age of 8 years and in boys before the age of 9 years. In addition to the psychological and physiological changes that occur because of entering puberty too early, there is the risk of the child failing to reach his or her full adult height. Therefore, leuprolide acetate's ability to suppress LH and sex steroid levels (testosterone and estradiol) to prepubertal levels is the reason that leuprolide acetate is approved for use in treating children with this disease. Use of this drug in a child with precocious puberty will slow or stop that child's secondary sexual development, slow linear growth and skeletal maturation, and in girls, will bring about the cessation of menstruation.

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

Leuprorelin binds to the LHRH receptors and is rapidly degraded by peptidases, then excreted in the urine.