体内
化学
药代动力学
敌手
药理学
激素
促黄体激素
受体
药效学
内科学
医学
生物化学
生物
生物技术
作者
Hamid R. Hoveyda,Graeme L. Fraser,Marie‐Odile Roy,Guillaume Dutheuil,Frédéric Batt,Mohamed El Bousmaqui,Julien Korac,François Lenoir,Alexey Lapin,Sophie Noël,Sébastien Blanc
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI