The Quest for the Best Dual Orexin Receptor Antagonist (Daridorexant) for the Treatment of Insomnia Disorders. (28th October 2020)

• Record Type: Journal Article
• Authors: Boss, Christoph; Gatfield, John; Brotschi, Christine; Heidmann, Bibia; Sifferlen, Thierry; von Raumer, Markus; Schmidt, Gunther; Williams, Jodi T.; Treiber, Alexander; Roch, Catherine
• Is Part Of: ChemMedChem. Volume 15:Number 23(2020)
• Page Start: 2286
• Page End: 2305
• Publication Date: 2020-10-28
• Subjects: drug design -- orexin receptor antagonists -- insomnia -- G protein-coupled receptors -- structure-activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000453
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : 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. Herein we describe our efforts leading to the identification of daridorexant, which successfully finished two pivotal phase 3 clinical trials for the treatment of insomnia disorders.