Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)
Discovery and Optimization of Novel Antagonists to the Human Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part I)
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DOI：
10.1021/jm5017413
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发表时间：
2015-04-09
影响因子：
7.3
通讯作者：
Blanc, Sebastien
中科院分区：
文献类型：
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作者：
Hoveyda, Hamid R.;Fraser, Graeme L.;Blanc, Sebastien
神经激肽-3受体(NK3R)最近被认为是调节强直的脉动性促性腺激素释放激素(GnRH)释放的重要因素。因此，我们决定探索NK3R拮抗剂作为性激素紊乱的治疗药物，这种药物可能受益于降低GnRH的搏动性，从而降低血浆黄体生成素(LH)水平，并相应地减弱循环中雄激素和雌激素的水平。报道了高通量筛选(HTS)HIT中通过生物等位铅变化获得的一种新的N-酰基-三氮唑哌嗪NK3R拮抗剂化学型的发现和先导优化。伴随而来的拮抗剂生物活性和配体亲脂效率(LLE)参数的改善是先导优化工作的主要指导方针。提供了先进的铅类似物的例子，以证明这种化学类型可实现适当的药代动力学(PK)曲线，以及药代动力学-药效学(PKPD)相关性，以分析在作为初步体内疗效模型的去势大鼠和猴子中观察到的抑制促黄体生成素的趋势。
Neurokinin-3 receptor (NK3R) has recently emerged as important in modulating the tonic pulsatile gonadotropin-releasing hormone (GnRH) release. We therefore decided to explore NK3R antagonists as therapeutics for sex-hormone disorders that can potentially benefit from lowering GnRH pulsatility with consequent diminished levels of plasma luteinizing hormone (LH) and correspondingly attenuated levels of circulating androgens and estrogens. The discovery and lead optimization of a novel N-acyl-triazolopiperazine NK3R antagonist chemotype achieved through bioisosteric lead change from the high-throughput screening (HTS) hit is described. A concomitant improvement in the antagonist bioactivity and ligand lipophilic efficiency (LLE) parameter were the principal guidelines in the lead optimization efforts. Examples of advanced lead analogues to demonstrate the amenability of this chemotype to achieving a suitable pharmacokinetic (PK) profile are provided as well as pharmacokinetic-pharmacodynamic (PKPD) correlations to analyze the trends observed for LH inhibition in castrated rats and monkeys that served as preliminary in vivo efficacy models.