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Fezolinetant (ESN-364) Sale

(Synonyms: 非唑奈坦,ESN-364) 目录号 : GC30104

Fezolinetant (ESN-364) 是一种神经激肽 3 受体 (NK3R) 的拮抗剂,用于治疗更年期潮热。

Fezolinetant (ESN-364) Chemical Structure

Cas No.:1629229-37-3

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10mM (in 1mL DMSO)
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1mg
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5mg
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10mg
¥5,130.00
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25mg
¥10,260.00
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50mg
¥16,380.00
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100mg
¥26,520.00
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实验参考方法

Animal experiment:

On the day of the experiment, the NK3R antagonist ESN364 is formulated in physiological saline with 9% 2-hydroxypropyl-β-cyclodextrin at a concentration of 2 mg/mL. At 240 minutes after the initiation of blood sampling, ESN364 (1 mg/kg, n=5) or vehicle (n=5) is administered by an iv bolus injection at a dose volume of 0.5 mL/kg through the jugular cannulae, and the injected material is flushed into the animal with 5 mL of heparinized saline. Blood sampling resumes at the indicated intervals following this iv administration.

References:

[1]. Fraser GL, et al. The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle. Endocrinology. 2015 Nov;156(11):4214-25.

产品描述

Fezolinetant is an antagonist of the neurokinin 3 receptor (NK3R), used for the treatment of menopausal hot flushes.

Fezolinetant (ESN364, 1 mg/kg, iv bolus) reversibly inhibits the regular, pulsatile secretion of LH in the ovarectomized ewe. ESN364 represses the pulse pattern of LH in all treated animals. ESN364 (5 mg/kg, p.o.) lowers plasma LH, but not FSH, in the castrated monkey. ESN364 (10, 25, 50 mg/kg, orally) also blocks the LH surge and decreases ovarian hormone levels throughout the menstrual cycle in monkeys[1].

[1]. Fraser GL, et al. The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle. Endocrinology. 2015 Nov;156(11):4214-25.

Chemical Properties

Cas No. 1629229-37-3 SDF
别名 非唑奈坦,ESN-364
Canonical SMILES O=C(N1[C@H](C)C2=NN=C(C3=NC(C)=NS3)N2CC1)C4=CC=C(F)C=C4
分子式 C16H15FN6OS 分子量 358.39
溶解度 DMSO : ≥ 50 mg/mL (139.51 mM) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.7903 mL 13.9513 mL 27.9026 mL
5 mM 0.5581 mL 2.7903 mL 5.5805 mL
10 mM 0.279 mL 1.3951 mL 2.7903 mL
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Research Update

Fezolinetant in the treatment of vasomotor symptoms associated with menopause

Expert Opin Investig Drugs 2021 Jul;30(7):681-694.33724119 10.1080/13543784.2021.1893305

Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS).Areas covered: This narrative review summarizes the dataset accrued for Fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS.Expert opinion: Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the 'hot flash' response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.

Randomized Controlled Trial of Neurokinin 3 Receptor Antagonist Fezolinetant for Treatment of Polycystic Ovary Syndrome

J Clin Endocrinol Metab 2021 Aug 18;106(9):e3519-e3532.34000049 PMC8372662

Context: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. Objective: This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist Fezolinetant in PCOS. Methods: This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included Fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. Results: Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for Fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (P < .001 and P < .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for Fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (P < .001 and P = .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (P = .03 and P = .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (P < .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (P > .10). Fezolinetant was well tolerated. Conclusion: Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.

Drugs for the treatment of postmenopausal symptoms: Hormonal and non-hormonal therapy

Life Sci 2023 Jan 1;312:121255.36470539 10.1016/j.lfs.2022.121255

Postmenopausal symptoms are systemic symptoms associated with estrogen deficiency after menopause. At present, treatments for postmenopausal symptoms include hormonal therapy (HT) and non-HT. However, the optimal regimen for balancing the benefits and risks remains unclear. This article reviewed the characteristics, regimens, and side effects of drugs used in hormonal and non-HT. However, HT is still the most effective treatment with safety in early initiation since menopause onset. Nevertheless, it is essential to evaluate the risks of related chronic diseases and customize individualized treatments. Possible estetrol preparations and more types of Tissue Selective Estrogen Complex formulations are potential directions of drug development in the future of HT. Regarding non-HT, Fezolinetant, currently in phase III clinical trials, is poised to become a first-in-class therapy for vasomotor symptoms. Ospemifene, dehydroepiandrosterone (DHEA), and vaginal lasers can also be used for moderate-to-severe genitourinary syndrome of menopause. Recent data suggest a superior efficacy and safety of vaginal lasers, but more validated evidence of long-term tolerability is needed to respond to the United States Food and Drug Administration warning. Herbal medication commonly used in Asia is effective in alleviating menopausal symptoms; however, its adverse effects still require more detailed reports and standardized observation methods. This review contributes to a better understanding of drugs for the treatment of postmenopausal symptoms and provides useful information for clinical drug selection.

Fezolinetant findings can fuel future instrumentation inquiries

Menopause 2020 Dec;27(12):1347.33048862 10.1097/GME.0000000000001648

Effects of neurokinin 3 receptor antagonist Fezolinetant on hot flash-like symptoms in ovariectomized rats

Eur J Pharmacol 2021 Aug 15;905:174207.34048742 10.1016/j.ejphar.2021.174207

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist Fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of Fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of Fezolinetant (1-10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, Fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that Fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of Fezolinetant for the treatment of VMS associated with menopause.