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

被引：30

作者：

Hoveyda, Hamid R. ^{[1
]}

Fraser, Graeme L. ^{[1
]}

Roy, Marie-Odile ^{[1
]}

Dutheuil, Guillaume ^{[1
]}

Batt, Frederic ^{[1
]}

El Bousmaqui, Mohamed ^{[1
]}

Korac, Julien ^{[1
]}

Lenoir, Francois ^{[1
]}

Lapin, Alexey ^{[1
]}

Noel, Sophie ^{[1
]}

Blanc, Sebastien ^{[1
]}

机构：

[1] Euroscreen SA, B-6041 Gosselies, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 07期

关键词：

PLASMA-PROTEIN BINDING; PULSE FREQUENCY; DRUG DISCOVERY; SCHIZOPHRENIA; ENDOMETRIOSIS; GNRH;

D O I：

10.1021/jm5017413

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：3060 / 3082

页数：23

共 75 条

[1]

Hydrogen-bond acceptor and donor properties of divalent sulfur (Y-S-Z and R-S-H) [J].