Non-peptide GnRH Antagonist Research Articles

Non-surgical methods of regulation reproductive function and contraception males of domestic animals

The regulation of male reproductive function today is not limited to surgical castration; there are many other methods of controlling reproductive function. Non-surgical methods of controlling male reproductive function can be reversible and not reversible, i.e., reproductive function is preserved or completely suppressed. Castration of males or orchiectomy leads to irreversible sterility of the male, when the male completely loses the ability to reproduce. This operation can also entail some side effects: obesity, underdevelopment of the external genital organs, an increased risk of diabetes or hypothyroidism, problems with frequent urination and behavioral problems. Therefore, methods of non-surgical management of reproductive function and contraception in males are being actively developed. The article presents the latest methods of contraception and the management of the reproductive function of male domestic animals (cats, dogs): clinical application GnRH and agonists GnRH, Non-Peptide GnRH Antagonists, GnRH-Toxin Conjugate, GnRH Vaccines and other immune contraceptive vaccines, chemical sterilants for intratesticular injections, calcium chloride, zinc gluconate, chlorhexidine digluconate, hypertonic saline, sex steroids (progestines), gene silencing, kisspeptin and GnIH, targeting delivery of cytotoxins, single-dose hormonal male and female sterilianr, FSH – receptor ligand cytotoxin conjugates, Sperm Protein Reactive with Antisperm Antibodies (SPRASA) Reversible Inhibition of Sperm under Guidance(RISUG).

Treatment of Breast Cancer With Gonadotropin-Releasing Hormone Analogs.

Although significant progress has been made in the implementation of new breast cancer treatments over the last three decades, this neoplasm annually continues to show high worldwide rates of morbidity and mortality. In consequence, the search for novel therapies with greater effectiveness and specificity has not come to a stop. Among the alternative therapeutic targets, the human gonadotropin-releasing hormone type I and type II (hGnRH-I and hGnRH–II, respectively) and its receptor, the human gonadotropin-releasing hormone receptor type I (hGnRHR-I), have shown to be powerful therapeutic targets to decrease the adverse effects of this disease. In the present review, we describe how the administration of GnRH analogs is able to reduce circulating concentrations of estrogen in premenopausal women through their action on the hypothalamus–pituitary–ovarian axis, consequently reducing the growth of breast tumors and disease recurrence. Also, it has been mentioned that, regardless of the suppression of synthesis and secretion of ovarian steroids, GnRH agonists exert direct anticancer action, such as the reduction of tumor growth and cell invasion. In addition, we discuss the effects on breast cancer of the hGnRH-I and hGnRH-II agonist and antagonist, non-peptide GnRH antagonists, and cytotoxic analogs of GnRH and their implication as novel adjuvant therapies as antitumor agents for reducing the adverse effects of breast cancer. In conclusion, we suggest that the hGnRH/hGnRHR system is a promising target for pharmaceutical development in the treatment of breast cancer, especially for the treatment of advanced states of this disease.

Long-term Effect of Elagolix on Bone Mineral Density in Women with Endometriosis-Associated Pain [38G

INTRODUCTION: To evaluate the long-term effect of elagolix, an oral, non-peptide GnRH antagonist, on bone mineral density (BMD) in two 6-month (M) extension studies (Elaris EM-III and IV) of the pivotal, 6M, phase 3 studies (12M overall treatment with 150mg once daily [QD] or 200mg twice daily [BID]). METHODS: Women with moderate/severe endometriosis-associated pain and a baseline BMD Z-score >-1.5 were randomized to receive elagolix in the pivotal studies and continued elagolix treatment in the extension studies (treated: Elaris EM-III, n=287; Elaris EM-IV, n=282). Total hip BMD was measured by dual energy X-ray absorptiometry and reviewed/evaluated by a blinded central reader. Baseline was before dosing in pivotal studies. RESULTS: After 6M of elagolix treatment in the pivotal studies, the proportion of women with a decrease in total hip BMD ≥8% ranged 0–1.1% across doses/studies; these women were not eligible for extension study. Following 12M treatment, the proportion of women with a total hip BMD decrease from baseline ≥8% was 1.8% (n=2) at 150mg QD and 0.9% (n=1) at 200mg BID in Elaris EM-III and 0% (n=0) at 150mg QD and 4.6% (n=5) at 200mg BID in Elaris EM-IV. For total hip, the mean BMD Z-score at extension-M6 was within the normal range of -2.0 to +2.0 across doses/studies; no women had a total hip BMD Z-score ≤-2. CONCLUSION: In women with endometriosis-associated pain, long-term elagolix treatment was associated with decreases in total hip BMD, while the mean total hip BMD Z-score was within the normal range and no women had a total hip BMD Z-score ≤-2.

Baseline Burden of Endometriosis-Associated Pain among Women in Two Phase 3 Elagolix Studies [10Q

INTRODUCTION: Few data exist on the extent of symptoms in women with endometriosis. This analysis examined baseline pain burden among women with moderate to severe endometriosis pain in two phase 3 studies of elagolix (an oral, non-peptide GnRH antagonist) for the management of endometriosis-associated pain. METHODS: Elaris EM-I and Elaris EM-II were two double-blind, randomized, 6-month, placebo-controlled phase 3 studies evaluating two elagolix doses (150 mg once daily and 200 mg twice daily) in women with endometriosis-associated pain. This analysis included randomized women pooled across studies and treatment groups. Dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) scores were recorded in a daily electronic-diary and characterized as ‘none’, ‘mild’, ‘moderate’, and ‘severe’, with definitions that incorporated daily functioning. Days with DYS or NMPP and severity of pain are summarized. Baseline was defined as the average of the last 35 days during the screening period. RESULTS: At baseline, the mean [SD] number of days women reported DYS and NMPP was 8.0 [3.0] days (97.6% of menstruating days) and 20.5 days [5.4] (90.3% of non-menstruating days), respectively (N=1686 for the combined studies). Enrolled women reported moderate/severe DYS and NMPP most days during the baseline phase (mean [SD]: DYS, 80.5% [21.2] of menstruating days; NMPP, 57% [29.0] of non-menstruating days). CONCLUSION: On average in these two phase 3 studies, women with endometriosis-associated pain experienced DYS or NMPP > 90% of days during the baseline phase and moderate/severe pain was reported for a majority of the days when pain was reported.

Long-Term Safety and Efficacy of Elagolix Treatment in Women With Endometriosis-Associated Pain [11OP

INTRODUCTION: Long-term safety and efficacy of elagolix, an oral, non-peptide GnRH antagonist for the management of endometriosis-associated pain, was evaluated in two 6-month (M) extension studies (Elaris EM-III and IV) of the pivotal, 6M, phase 3 studies (12M-overall treatment with 150 mg once daily [QD] or 200 mg twice daily [BID]). METHODS: Women with moderate/severe endometriosis-associated pain, randomized to receive elagolix in the pivotal studies, continued treatment during the extension studies (treated: Elaris EM-III, n=287; Elaris EM-IV, n=282). Baseline was before dosing in pivotal studies. Dysmenorrhea (DYS), non-menstrual pelvic pain (NMPP), and dyspareunia (DYSP) scores were recorded in a daily electronic-diary. Adverse events (AE), bone mineral density (BMD), and endometrium were assessed. RESULTS: DYS, NMPP and DYSP scores across dose groups were significantly decreased compared to placebo at M6 in the pivotal studies (P<.05; exception-DYSP 150 mg), and improvements in scores were maintained after 12M of treatment in Elaris EM-III (Extension-M6 mean percent change from baseline: DYS, 150 mg QD=−49%, 95% CI [−57,−41], 200 mg BID=−82%, 95% CI [−88,−76], NMPP, 150 mg QD=−49, 95% CI [−57,−41], 200 mg BID=−57%, 95% CI [−64,−49]; DYSP, 150 mg QD=−31%, 95% CI [−46,−16], 200 mg BID=−42%, 95% CI [−58,−25]). Hot flush was the most common AE over 12M of treatment (150 mg QD=29.5%; 200 mg BID=52.2%). At extension M6, there was a dose-dependent decrease in BMD from baseline, while mean lumbar spine BMD Z-score was within normal range (−2.0–+2.0). Mean change in endometrial thickness ranged 0.6 to −0.8 mm across doses. Elaris EM-IV results were generally similar. CONCLUSION: In women with endometriosis-associated pain, long-term elagolix treatment was associated with reductions in DYS, NMPP, and DYSP. No new safety concerns were identified with long-term elagolix use.

Recent Development of Non-Peptide GnRH Antagonists.

The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited issues associate with peptide agonists and antagonists have however, led to significant interest in developing orally active, small molecule, non-peptide antagonists. In this review, we will summarize all developed small molecule GnRH antagonists along with the most recent clinical data and therapeutic applications.

Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males

TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment. The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone. This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers. Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years. Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone. Oral TAK-385 was readily absorbed, and steady state was reached in ≤ 14 days. Food reduced TAK-385 systemic exposure by 47-52%. Mean serum testosterone levels declined ≤ 6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥ 7 to <3 days. TAK-385 doses ≥ 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤ 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤ 2). Oral TAK-385 (40-180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone-sensitive prostate cancer are 80 and 120 mg/d.

Petal study: safety, tolerability and effectiveness of elagolix, an oral GnRH antagonist for endometriosis

OBJECTIVE: Estradiol (E2) suppression reduces signs and symptoms of endometriosis. A dose-related partial suppression of E2 and reduction of pain associated with endometriosis have been achieved in 3-month studies with an oral, non-peptide GnRH antagonist, elagolix (NBI-56418). The Petal study assessed treatment impact on bone mineral density, secondary endpoints assessed tolerability, safety and effectiveness of elagolix during 6-month's treatment and 6-month's follow up.

Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix

Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. Fifty-five healthy, regularly cycling premenopausal women participated. Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses. Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.

Pharmacological Characterization of a Novel Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor, NBI-42902

Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.

Suppression of Serum Luteinizing Hormone in Postmenopausal Women by an Orally Administered Nonpeptide Antagonist of the Gonadotropin-Releasing Hormone Receptor (NBI-42902)

Parenteral administration of peptide GnRH analogs is widely used in clinical practice for the suppression of pituitary gonadotropins. NBI-42902 is an orally available, high-affinity nonpeptide antagonist of the human GnRH receptor. The objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropin secretion of NBI-42902 in postmenopausal women. This was a phase I, double-blind, placebo-controlled, single-dose study with sequential dose escalation. Fifty-six healthy, postmenopausal women were included. FSH levels were greater than 40 IU/liter, and body mass index was within 20% of ideal values for all subjects. Subjects were administered 5, 10, 25, 50, 75, 100, 150, or 200 mg NBI-42902 as an oral solution. Safety, tolerability, and serum LH and FSH concentrations were evaluated. NBI-42902 was well tolerated. Serum LH concentrations rapidly declined, and dose-dependent suppression was observed. Maximal change from baseline LH concentrations ranged from -19 +/- 5% in the 5-mg group to -55 +/- 2% in the 150-mg group. Suppression of FSH was less pronounced (-15 to -22% of baseline). NBI-42902 was rapidly absorbed after oral administration with a terminal elimination half-life ranging from 2.7 +/- 0.3 to 4.8 +/- 0.8 h. A clear relationship between plasma NBI-42902 concentrations and LH suppression was evident. Dose-dependent LH suppression was achieved by oral administration of a nonpeptide GnRH antagonist suggesting that compounds such as NBI-42902 may enable adjustable gonadotropin suppression as part of novel treatment strategies for benign gynecological conditions.

GnRHs and GnRH receptors

GnRH is the pivotal hypothalamic hormone regulating reproduction. Over 20 forms of the decapeptide have been identified in which the NH2- and COOH-terminal sequences, which are essential for receptor binding and activation, are conserved. In mammals, there are two forms, GnRH I which regulates gonadotropin and GnRH II which appears to be a neuromodulator and stimulates sexual behaviour. GnRHs also occur in reproductive tissues and tumours in which a paracrine/autocrine role is postulated. GnRH agonists and antagonists are now extensively used to treat hormone-dependent diseases, in assisted conception and have promise as novel contraceptives. Non-peptide orally-active GnRH antagonists have been recently developed and may increase the flexibility and range of utility. As with GnRH, GnRH receptors have undergone co-ordinated gene duplications such that cognate receptor subtypes for respective ligands exist in most vertebrates. Interestingly, in man and some other mammals (e.g. chimp, sheep and bovine) the Type II GnRH receptor has been silenced. However, GnRH I and GnRH II still appear to have distinct roles in signalling differentially through the Type I receptor (ligand-selective-signalling) to have different downstream effects. The ligand–receptor interactions and receptor conformational changes involved in receptor activation have been partly delineated. Together, these findings are setting the scene for generating novel selective GnRH analogues with potential for wider and more specific application.

Identification of neutral 4- O-alkyl quinolone nonpeptide GnRH receptor antagonists

A series of neutral, nonbasic quinolone GnRH antagonists were prepared via Mitsunobu alkylation of protected and unprotected 4-hydroxy quinolone intermediates. The synthetic route was improved by utilization of unique reactivity and convergency afforded by the use of mono and bis-trimethylsilylethyl protected quinolones. Potent neutral GnRH antagonists were identified, including ether and lactam derivatives, that show similar in vitro binding affinity and functional activity as compared to the earlier basic 4-aminoalkyl quinolone series of nonpeptide GnRH antagonists.

Male hormonal contraception

Male hormonal contraception, based on the suppression of both gonadotropins, follicle-stimulating hormone and luteinizing hormone, resulting in marked decrease in sperm production, is designed for couples in stable relationships where the male partner desires to assume family planning responsibilities using reversible methods. Two large scale, multicenter studies that used testosterone injections as the prototype male hormonal contraceptive demonstrated when azoospermia and/or very severe oligozoospermia were attained, contraceptive efficacy was equivalent to female hormonal methods. Current studies aim to find the androgen alone or androgen plus progestin preparations that are most efficacious, user friendly, and with least potential adverse effects. It is likely that injections or implants of androgens either alone or with progestins will become the first male hormonal contraceptive available within this decade. Further research and development include the use of selective androgen and/or progestin receptor modulators, nonpeptide GnRH antagonists, and agents with local actions on the testis for male contraception.