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

Struthers, R. Scott; Xie, Qui; Sullivan, Susan K.; Reinhart, Greg J.; Kohout, Trudy A.; Zhu, Yunfei; Chen, Chen; Liu, Xin-Jun; Ling, Nicholas; Yang, Weidong; Maki, Richard A.; Bonneville, Anne K.; Chen, Takung; Bozigian, Haig

doi:10.1210/en.2006-1213

Cited by 29 publications

(30 citation statements)

References 42 publications

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“…ESN364 has similar oral efficacy and potency to the small-molecule GnRH antagonist Elagolix (NBI-42902) to lower plasma LH in castrated monkeys (47). However, the relevant clinical concern for GnRH modulators is the adverse event profile in which a potential comparative advantage for NK3R vs GnRH antagonists can be envisaged.…”

Section: Discussionmentioning

confidence: 99%

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

et al. 2015

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Women's health disorders such as uterine fibroids and endometriosis are currently treated by GnRH modulators that effectively suppress the hypothalamic-pituitary-gonadal axis. The neurokinin-3 receptor (NK3R) is an alternative target with an important role in the modulation of this axis. In this report, we demonstrate that systemic administration of an NK3R antagonist (ESN364) prolongs the LH interpulse interval in ovarectomized ewes and significantly lowers plasma LH and FSH concentrations in castrated nonhuman primates (Macaca fascicularis). Moreover, daily oral dosing of ESN364 throughout the menstrual cycle in M fascicularis lowered plasma estradiol levels in a dose-dependent manner, although nadir levels of estradiol were maintained well above menopausal levels. Nevertheless, estradiol levels during the follicular phase were sufficiently inhibited at all doses to preclude the triggering of ovulation as evidenced by the absence of the LH surge and failure of a subsequent luteal phase rise in plasma progesterone concentrations, consistent with the absence of normal cycle changes in the uterus. Apart from the point at surge, FSH levels were not altered over the course of the menstrual cycle. These effects of ESN364 were reversible upon cessation of drug treatment. Together these data support the proposed role of neurokinin B-NK3R signaling in the control of pulsatile GnRH secretion. Furthermore, in contrast to GnRH antagonists, NK3R antagonists induce a partial suppression of estradiol and thereby offer a viable therapeutic approach to the treatment of ovarian sex hormone disorders with a mitigated risk of menopausallike adverse events in response to long-term drug exposure. (Endocrinology 156: 4214 -4225, 2015)

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Section: Discussionmentioning

confidence: 99%

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

et al. 2015

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“…In vivo studies were, therefore, performed in monkeys, where the affinity for the GnRH receptor was only sixfold lower (K i ¼ 3.5 nM). 59,60 Oral administration of 100 mg/kg 41 completely suppressed LH blood levels over 24 hr in castrated male macaques. A final optimization study was performed to improve the manufacturing reproducibility, as 41 showed stereoisomerism due to the 6-methyl group.…”

Section: G Furamide Derivativesmentioning

confidence: 99%

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Heitman

IJzerman

2008

Medicinal Research Reviews

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The hypothalamic-pituitary-gonadal (HPG) axis, important in reproduction and sex hormone-dependent diseases, is regulated by a number of G protein-coupled receptors. The recently "deorphanized" GPR54 receptor activated by the peptide metastin is thought to be the key regulator of the axis, mainly by releasing gonadotropin-releasing hormone (GnRH) from the hypothalamus. The latter decapeptide, through the activation of the GnRH receptor in the anterior pituitary, causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently activate their respective receptors on the gonadotrope cells. In this review we will discuss the small molecule agonists and antagonists that are currently being developed to intervene with the action of these four receptors. For GnRH receptors, 14 different chemical classes of non-peptidic antagonists have been reported, while for the LH receptor three classes of agonists have been described. Both agonists and antagonists have been introduced for the FSH receptor. Recently, the first non-peptidic agonist for GPR54 was reported.

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“…49 Nevertheless, the requirement for frequent parenteral administration and the high cost of such agents make them impractical as a MCM. The development of non-peptidic antagonists suitable for oral administration 50 or slow-release implants (histrelin) may reignite interest in testing these substances. 51…”

Section: Combination Of Androgens With Gnrh-analoguesmentioning

confidence: 99%

Male contraception: a clinically-oriented review

Kanakis

Goulis

2015

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Despite the variety of available female contraceptive methods, many pregnancies (~50%) are still undesired. Many men (>60%) want to participate equally with their partner in family planning; however, male contraceptive methods (MCMs) account for only 14% of those used worldwide and no pharmaceutical MCM is available so far. The only two MCMs currently available are condoms, which despite protecting against sexually transmitted diseases have high failure rates (~19%), and vasectomy, which though very efficient (99%) is poorly reversible (<50%). Among MCMs under investigation, male hormonal contraceptives (MHCs) are those that have come closest to commercialization. The action of MHCs relies on the disruption of spermatogenesis that exogenous androgen administration evokes by suppressing the hypophyseal-gonadal axis. Various regimens of androgens as monotherapy or in combination with progestins have been tested in clinical trials achieving a Pearl Index <1.0 (equal to that of the female oral contraceptive pill); however, concerns regarding the variable response rates observed (non-responders: 5-20%), the impracticality of parenteral administration and long-term prostate-associated or cardiovascular morbidity have deflected the interest of the pharmaceutical industry from further research. Non-hormonal contraception methods may be, at least theoretically, more specific by selectively disrupting spermatogenesis and sperm transport or fertilizing ability. Nevertheless, only a few have been tested in clinical trials (Reversible Inhibition of Sperm Under Guidance, RISUG, and Intra Vas Plugs); most of them are still in pre-clinical development or have been abandoned due to toxicity (gossypol). Consequently, until a reliable, safe and practical MCM is developed, women will continue to bear most of the contraception burden.

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

Cited by 29 publications

References 42 publications

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

G protein‐coupled receptors of the hypothalamic–pituitary–gonadal axis: A case for gnrh, LH, FSH, and GPR54 receptor ligands

Male contraception: a clinically-oriented review

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