The quest for the best dual orexin receptor antagonist (daridorexant) for the treatment of insomnia disorders

Since its discovery in 1998, the orexin system is 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 the orexin 2-receptor and two neuropeptides with agonistic effects, the orexin A and the orexin B-peptide. 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 ( 93 ) currently in phase 3 clinical trials for the treatment of insomnia disorders.