Discovery and Preclinical Development of Orally Active Small Molecules that Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism.
Discovery and Preclinical Development of Orally Active Small Molecules that Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism.
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DOI：
10.3389/fphar.2020.602593
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发表时间：
2020
影响因子：
5.6
通讯作者：
Palmer S
中科院分区：
文献类型：
--
作者：
Nataraja S;Yu H;Guner J;Palmer S
口服活性促卵泡激素受体变构激动剂将为超过 1600 万育龄不孕妇女提供低复杂性方法（诱导排卵 - 宫内授精）或高复杂性方法（受控卵巢刺激 - 体外受精）的首选治疗。我们提出了两种口服促卵泡激素受体变构激动剂化合物，它们具有临床使用所需的药理学、药物代谢、药代动力学和安全性。这些分子提供了适合排卵诱导-宫内授精或受控卵巢刺激-体外受精的单一药物，对患者来说更方便，并实现了与rec-hFSH相似的临床前疗效。在转染单个糖蛋白受体的中国仓鼠卵巢细胞中对 TOP5668、TOP5300 进行体外评估，测量 cAMP（FSHR、LH/CGR、促甲状腺激素受体）。发现 TOP5668 仅具有促卵泡激素受体变构激动剂活性，而发现 TOP5300 具有混合促卵泡激素受体变构激动剂和 LHR-AA 活性。在存在或不存在低剂量rec-hFSH的情况下，两种化合物均刺激培养的大鼠颗粒细胞产生雌二醇，且呈浓度依赖性增加，而只有TOP5300刺激大鼠原代Leydig细胞产生睾酮。在从接受受控卵巢刺激体外受精的患者中获得的汇集的人颗粒细胞中，TOP5300 刺激的最大雌二醇反应是 rec-hFSH 的 7 倍，而 TOP5668 的效力是 TOP5300 的 10 倍。 TOP5300和TOP5668均刺激未成熟大鼠的卵泡发育，其功效与重组卵泡刺激素相同。在使用 TOP5300 治疗的小鼠中，在低剂量卵泡刺激素存在的情况下，使用 TOP5300 和低剂量卵泡刺激素的小鼠与参考蛋白孕马血清促性腺激素或高剂量 rec-hFSH 的小鼠的卵母细胞数量、受精率和孵化囊胚率没有差异。 ADME/PK 和安全性良好。此外，在对大鼠或狗进行的 14 天毒理学研究中，TOP5300 对甲状腺激素没有明显的活性。与 re-hFSH 相比，所选的先导化合物 TOP5300 刺激多囊卵巢综合征患者的颗粒叶黄素细胞产生更强劲的雌二醇。结论：在临床前研究中发现两种新型口服 FSHR 变构激动剂 TOP5668 和 TOP5300 能够模仿 re hFSH 的生物活性。这两种化合物都会导致大鼠和小鼠的卵泡发生和超数排卵。具体来说，与rec-hFSH相比，TOP5300在小鼠中产生相似数量的排卵卵母细胞，这些卵母细胞受精并发育成孵化的囊胚。安全性表明没有毒性。
An orally active follicle stimulating hormone receptor allosteric agonist would provide a preferred treatment for over 16 million infertile women of reproductive age in low complexity methods (ovulation induction-intrauterine insemination) or in high complexity methods (controlled ovarian stimulation-in vitro fertilization). We present two oral follicle stimulating hormone receptor allosteric agonist compounds that have the desired pharmacology, drug metabolism, pharmacokinetics, and safety profile for clinical use. These molecules provide a single agent suitable for ovulation induction-intrauterine insemination or controlled ovarian stimulation-in vitro fertilization that is more convenient for patients and achieves similar preclinical efficacy as rec-hFSH. TOP5668, TOP5300 were evaluated in vitro in Chinese hamster ovary cells transfected with individual glycoprotein receptors measuring cAMP (FSHR, LH/CGR, thyroid stimulating hormone receptor). TOP5668 was found to have solely follicle stimulating hormone receptor allosteric agonist activity while TOP5300 was found to have mixed follicle stimulating hormone receptor allosteric agonist and LHR-AA activity. Both compounds stimulated concentration-dependent increases in estradiol production from cultured rat granulosa cells in the presence or absence of low dose rec-hFSH, while only TOP5300 stimulated testosterone production from rat primary Leydig cells. In pooled human granulosa cells obtained from patients undergoing controlled ovarian stimulation-in vitro fertilization, TOP5300 stimulated 7-fold greater maximal estradiol response than rec-hFSH and TOP5668 was 10-fold more potent than TOP5300. Both TOP5300 and TOP5668 stimulated follicular development in immature rat to the same efficacy as recombinant follicle stimulating hormone. In mice treated with TOP5300, in the presence of low dose of follicle stimulating hormone, there were no differences in oocyte number, fertilization rate, and hatched blastocyst rate in mice with TOP5300 and low dose follicle stimulating hormone vs. reference proteins pregnant mare serum gonadotropin or high dose rec-hFSH. ADME/PK and safety profiles were favorable. In addition, there was no appreciable activity on thyroid hormones by TOP5300 in 14-days toxicological study in rat or dog. The selected lead compound, TOP5300 stimulated a more robust increase in estradiol production from granulosa-lutein cells from women with polycystic ovarian syndrome patient compared to rec-hFSH. Conclusions: Two novel oral FSHR allosteric agonist, TOP5668 and TOP5300, were found to mimic the biological activity of rec hFSH in preclinical studies. Both compounds led to folliculogenesis and superovulation in rat and mice. Specifically, TOP5300 led to a similar number of ovulated oocytes that fertilized and developed into hatched blastocysts in mice when compared to rec-hFSH. The safety profile demonstrated lack of toxicity.
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影响因子：
4.1
作者：
Hoogendoorn S;van Puijvelde GHM;van der Marel GA;van Koppen CJ;Timmers CM;Overkleeft HS
通讯作者：
Overkleeft HS
影响因子：
4
作者：
Breckwoldt, M.;Selvaraj, N.;Amsterdam, A.
通讯作者：
Amsterdam, A.
影响因子：
6.1
作者：
Fauser, BCJM;Chang, J;Lobo, R
通讯作者：
Lobo, R
影响因子：
6.7
作者：
Cozzolino, Mauro;Vitagliano, Amerigo;Garcia-Velasco, Juan Antonio
通讯作者：
Garcia-Velasco, Juan Antonio
DOI：
10.1073/pnas.1206643109
发表时间：
2012-07-31
影响因子：
11.1
作者：
Jiang, Xuliang;Liu, Heli;He, Xiaolin
通讯作者：
He, Xiaolin