Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)

Hoveyda, Hamid R.; Fraser, Graeme L.; Roy, Marie‐Odile; Dutheuil, Guillaume; Batt, Frédéric; Bousmaqui, Mohamed El; Korac, Julien; Lenoir, François; Lapin, Alexey; Noël, Sophie; Blanc, Sébastien

doi:10.1021/jm5017413

Cited by 36 publications

(43 citation statements)

References 70 publications

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“…NK3R antagonist pharmacology on ovarian hormones is explained in the context of drug effects in the arcuate nucleus modulating GnRH pulse frequency, a concept consistent with our findings on the LH pulse frequency, the differential effects on LH and FSH in intact females, and the importance of adequate potency-normalized, free drug concentrations in brain and plasma to achieve in vivo efficacy (11,13). However, it is noted that NKB/NK3R mRNA is also expressed in human mural granulosa cells (54) and the myometrium (55), with significantly elevated expression in leiomyomas (eg, uterine fibroids, [56]).…”

Section: Discussionsupporting

confidence: 79%

“…Previously we have reported that the peripheral administration of NK3R antagonists, including ESN364, decreases plasma LH levels in castrate rat and monkey in a manner demonstrating a clear correlation between pharmacodynamics (PD) and pharmacokinetics (PK) of potency-normalized free drug concentrations in the plasma and brain, respectively (11,13). Here we extend these findings by demonstrating in OVX ewe that the diminution of plasma LH levels is specifically due to an interruption of the LH pulse.…”

Section: Discussionsupporting

confidence: 78%

“…All clinical development candidates were discontinued due to lack of efficacy, which was interpreted as a consequence of poor drug availability at the central sites of action (12). Our comparison of the effects of these previous generation NK3R antagonists with ESN364 in the modulation of the HPG axis has demonstrated that compound efficacy in lowering plasma LH in the castrate rat correlates well with the potency-normalized free drug concentrations in plasma and brain and that this aspect is key to the superior profile of ESN364 in modulating the HPG axis (11,13).…”

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confidence: 92%

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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: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 78%

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confidence: 92%

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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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“…Numerous studies indicated that the function of NK3R related to tachykinins exert a plethora of biological effects, including smooth muscle contraction and relaxation, vasodilatation, secretion, activation of the immune system, pain transmission and neurogenic inflammation, and are implicated in a broad range of CNS disorders [27, 28]. Here, we described further evidence that NKB could function as an endogenous angiogenesis inhibitor.…”

Section: Discussionsupporting

confidence: 55%

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

et al. 2017

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Angiogenesis is essential for tumor growth and metastasis, controlling angiogenesis is a promising strategy in cancer treatment. However, thus farther severe side effects of anti-angiogenic drugs have been rather demonstrated, stimulating interest in seeking novel targets of anti-angiogenesis. Neurokinin receptors, also known as tachykinin receptors, are usually considered as drug targets due to diverse physiological functions and their tractability. Although Neurokinin B, the selective natural agonist of neurokinin-3 receptor, have been shown to exhibit anti-angiogenesis activity, the effect and mechanism of neurokinin-3 receptor-mediated angiogenesis still remains unclear. In the present study, we demonstrated that [Mephe7]NKB, an analogue of NKB, possess significant anti-angiogenic effect on CAM. Furthermore, by introducing the tumor angiogenesis homing sequence (NGR), we designed and synthesized two novel agonist analogues of NK3R, NK3R-A1 and NK3R-A2. Both of the two analogues exhibit more efficient anti-migration effect on HUVECs by activating NK3R in vitro, and showed potent antitumor activities with no significant side effects in vivo. Taken together, our results illuminated that NK3R might be a potential novel target for the anti-angiogenesis therapy. Notably, NK3R-A1 might be used as a template for the development of the anti-tumor drugs on the basis of the anti-angiogenesis strategy.

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“…Due to the spacial similarity of vinyl groups to ring embedded sulfur atoms thiadiazoles can be considered isosteres of diazines 5,6 adding to their potential to serve as fragments of bioactive structures. [7][8][9][10] Thiadiazoles can occur in four distinct regioisomeric forms (1)(2)(3)(4) enriching their structural diversity with respect to local polarization and vector space occupied by both carbon bound substituents R 1 and R 2 ( Figure 1). …”

Section: Introductionmentioning

confidence: 99%

A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles

Baumann

Baxendale

2017

Bioorganic & Medicinal Chemistry

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Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)

Cited by 36 publications

References 70 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

Targeting neurokinin-3 receptor: a novel anti-angiogenesis strategy for cancer treatment

A continuous flow synthesis and derivatization of 1,2,4-thiadiazoles

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