The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders

被引：30

作者：

Boss, Christoph ^{[1
]}

Gatfield, John ^{[1
]}

Brotschi, Christine ^{[1
]}

Heidmann, Bibia ^{[1
]}

Sifferlen, Thierry ^{[1
]}

von Raumer, Markus ^{[1
]}

Schmidt, Gunther ^{[1
]}

Williams, Jodi T. ^{[1
]}

Treiber, Alexander ^{[1
]}

Roch, Catherine ^{[1
]}

机构：

[1] Idorsia Pharmaceut Ltd, Drug Discovery & Preclin Res & Dev, Hegenheimermattweg 91, CH-4123 Allschwil, BL, Switzerland

来源：

CHEMMEDCHEM | 2020年 / 15卷 / 23期

关键词：

drug design; orexin receptor antagonists; insomnia; G protein-coupled receptors; structure-activity relationships; SELECTIVE AGONIST; SLEEP; DISCOVERY; ZOLPIDEM; POTENT; HYPOCRETINS; NONPEPTIDE; SYMPTOMS; PARADIGM; TAK-925;

D O I：

10.1002/cmdc.202000453

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein-coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling([1]) and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.

引用

页码：2286 / 2305

页数：20

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